Aqueous compositions of poorly water-soluble compounds

Abstract

Aqueous emulsions that are substantially or completely devoid of an oil phase. An embodiment combines a diethylene glycol monoethyl ether (DEGEE) with polyglyceryl-10 caprylate. Another embodiment combines dimethyl isosorbide (DMI) with polyglyceryl-10 caprylate or a polyethylene glycol (PEG: H(OCH2CH2)nOH) derivative of castor oil, wherein n is 2 to about 1,000. The aqueous emulsions can be used as a platform to solubilize poorly water-soluble chemical compounds for use in a variety of fields, including the pharmaceutical, cosmetic, skin care, personal care, food, and industrial arenas. The aqueous emulsions can be delivered to a human or animal via a variety of modes for personal care, hygiene or to treat a diverse number of ailments.

Description

[0001] AQUEOUS COMPOSITIONS OF POORLY WATER-SOLUBLE COMPOUNDS

[0002] RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. §119(e) to (i) U.S. Provisional Patent Application No. 63 / 564,826, filed March 13, 2024, and (ii) U.S. Provisional Patent Application 63 / 720,953, filed November 15, 2024, each of which is incorporated herein by reference.

[0004] BACKGROUND OF THE INVENTION

[0005] Emulsions are compositions that are used in a variety of industrial, cosmetic, personal care, skin care, and pharmaceutical products, including ocular, topical, mucosal, intravenous, intramuscular, sublingual, and oral products. Emulsions are employed as precursors to prepare polymer microparticles, solid lipid nano-particles, inorganic nano-particles, oil-filled micro-capsules, and magnetic particles for imaging, diagnostics, and drug delivery. Even with their widespread use, they remain an underutilized drug product format, particularly, for poorly water-soluble chemical compounds.

[0006] It can be challenging to combine a poorly water-soluble chemical compound in a water-based system. Formulators in the biological, chemical, pharmaceutical, cosmetic, and other industries have developed several methods to overcome this challenge. One of the more studied methods is to form an emulsion colloid by mixing an oil phase with a water phase in combination with an emulsifying agent. This type of emulsion colloid generally has an oil phase, a water phase, and a surfactant or other emulsifier, and may also contain a co-solvent to aid in solubilizing the poorly water-soluble chemical compound.

[0007] Oil and water are immiscible liquids that do not form a homogeneous mixture when added together. However, when mixed with an emulsifying agent, they can form an emulsion (e.g., oil-in- water, water-in-oil, or a water-in-oil-in-water triple emulsion) in which a poorly water-soluble (and oilsoluble) chemical compound can be dispersed in a continuous medium. An emulsion is a thermodynamically stable isotropic system in which two immiscible liquids (e.g., oil and water) are mixed to form a single dispersion by means of an emulsifying agent (e.g., surfactant + co-surfactant). One of the immiscible liquids is dispersed in the form of very small globules (internal phase) throughout the other immiscible liquid (external phase) forming a continuous medium. The resulting emulsion is a kinetically stable and usually clear (i.e., transparent or translucent) dispersion of two immiscible phases in a continuous medium. Even though the liquids that form them may be clear, emulsions can appear cloudy or colored because light is scattered by suspended particles in the mixture.

[0008] A poorly water-soluble chemical compound can detrimentally affect the appearance, stability, and efficacy of the compound in the product. Active chemical compounds that are poorly water-soluble may exhibit diminished bioavailability in a product (e.g., a pharmaceutical, cosmetic or food product), especially in products with high water concentrations. Some active compounds cannot be orally dosed because they are not effective or can cause harm (e.g., fast metabolism due to short half-life, toxicity issues, side effects, etc.). Oil-in-water and water-in-oil emulsions comprising oil, water, surfactants (or other emulsifying agents), and co-solvents have been formulated and studied with poorly water-soluble active ingredients. These studies have demonstrated a general need for having an oil phase in a composition for forming an aqueous based emulsion system containing one or more different types of poorly water-soluble active and inactive compounds.

[0009] Notwithstanding the varied kinds of formulations that have been developed, their effectiveness and side effects have been less than desirable. There is a demand for better formulations to effectively deliver poorly water-soluble active and inactive chemical compounds to a human or an animal. Thus, there is a need for improved formulations containing poorly water-soluble active and inactive chemical compounds, particularly, new aqueous based topical compositions containing poorly water-soluble active and inactive chemical compounds.

[0010] SUMMARY

[0011] Described herein is an aqueous emulsion composition that is substantially or completely devoid of an oil phase, wherein the aqueous emulsion comprises a combination of:

[0012] (i) about 50% to about 92% by weight of water;

[0013] (ii) about 0.1% to about 50% by weight of di ethylene glycol monoethyl ether (DEGEE);

[0014] (iii) about 1% to about 30% by weight of poly glyceryl- 10 caprylate; and

[0015] (iv) about 0.01% to about 2% by weight of a poorly water-soluble chemical compound; wherein the water functions as a continuous aqueous dispersion medium and ingredients (ii),

[0016] (iii), and (iv) function as a liquified dispersed phase in the aqueous emulsion that is substantially or completely devoid of an oil phase.

[0017] Ingredients (ii), (iii), and (iv) are not considered an oil phase with respect to the inventive aqueous emulsion composition.

[0018] Further described herein is an aqueous emulsion that substantially or completely lacks an oil phase, the aqueous emulsion comprising a combination of:

[0019] (i) about 50% to about 92% by weight of water;

[0020] (ii) about 0.1% to about 30% by weight of dimethyl isosorbide (DMI);

[0021] (iii) about 1% to about 30% by weight of poly glyceryl- 10 caprylate or about 5% to about 20% by weight of a polyethylene glycol (PEG: IfyOCEECEE^OH) derivative of castor oil, wherein n is 2 to about 1,000; and

[0022] (iv) about 0.01% to about 2% by weight of a poorly water-soluble chemical compound; wherein the water functions as a continuous aqueous dispersion medium and ingredients (ii), (iii), and (iv) function as a liquified dispersed phase in the aqueous emulsion that substantially or completely lacks an oil phase.

[0023] In an embodiment, the aqueous emulsion composition completely lacks an oil phase.

[0024] The substantially or completely oil phase-free aqueous emulsion may further comprise about 10% to about 49% by weight of a cleansing agent, a fragrance, an oil, and / or a thickening agent.

[0025] The substantially or completely oil phase-free emulsion can operate as a platform to deliver a poorly water-soluble chemical compound via a variety of ways, such as, orally, sublingually, topically, ocularly, mucosally, intravenously, intramuscularly, or via an infusion. It is particularly useful for topical cutaneous (skin) therapeutic applications.

[0026] The substantially or completely oil phase-free aqueous emulsion can be a macro-, mini-, micro- or nano- emulsion. The nano-emulsions may provide a d50 nano-particle size and a number weighted mean nano-particle size each of less than about 150 nm. Optimizing the loads of the ingredients in the composition can reduce or increase the particle size and droplet size.

[0027] The substantially or completely oil phase-free aqueous emulsion may be advantageously used for solubilizing poorly water-soluble active and inactive chemical compounds. In an embodiment, the active chemical compound can be a natural product, such as a flavonoid (e.g., flavanol or flavonol) or a polyphenol. Examples of active compounds include fisetin, / raws- resveratrol, a milk thistle extract comprising silymarin, quercetin, dihydroquercetin, curcumin, turmeric, (-)-epigallocatechin-3 -gallate (EGCG), rutin, salicylic acid, diosmin, imatinib, imatinib mesylate, an extract of Centipeda minima, or a mixture thereof.

[0028] In an embodiment, a topical skincare product may be produced from a substantially or completely oil phase-free aqueous emulsion that contains one or more of the following poorly water- soluble chemical compounds: fisetin, / raws- resveratrol, quercetin, dihydroquercetin, and / or rutin.

[0029] The invention further includes a method of formulating a substantially or completely oil phase- free aqueous emulsion for solubilizing poorly water-soluble chemical compounds.

[0030] The foregoing and other objects and features of the disclosure will become more apparent from the following detailed description. Further embodiments, forms, features, aspects, benefits, objects, and advantages of the invention shall become apparent from the detailed description.

[0031] DETAILED DESCRIPTION

[0032] The novel substantially or completely oil phase-free aqueous emulsion compositions described herein can be used as a platform to solubilize poorly water-soluble active and inactive ingredients. Below are definitions for some of the terms used in this disclosure. Definitions.

[0033] The following definitions are included to provide a clear and consistent understanding of the specification and claims. As used herein, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as one of skill in the art would understand. Such ordinary meanings may be obtained by reference to technical dictionaries, such as Hawley ’s Condensed Chemical Dictionary 16thEdition, authored by Michael Larranaga, Richard J. Lewis, Sr., and Robert Lewis, and published by John Wiley & Sons, Inc., New York, N.Y. (2016).

[0034] References in the specification to "one embodiment", "an embodiment", etc., indicate that the embodiment described may include a particular aspect, feature, structure, moiety, or characteristic, but not every embodiment necessarily includes that aspect, feature, structure, moiety, or characteristic. Moreover, such phrases may, but do not necessarily, refer to the same embodiment referred to in other portions of the specification. Eurther, when a particular aspect, feature, structure, moiety, or characteristic is described in connection with an embodiment, it is within the knowledge of one skilled in the art to affect or connect such aspect, feature, structure, moiety, or characteristic with other embodiments, whether or not explicitly described.

[0035] The singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, so that a compound X includes a plurality of compounds X. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for the use of exclusive terminology, such as "solely," "only," and the like, in connection with any element described herein, and / or the recitation of claim elements or use of "negative" limitations.

[0036] The term "and / or" means any one of the items, any combination of the items, or all of the items with which this term is associated. The phrase "one or more" is readily understood by one of skill in the art, particularly when read in context of its usage. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit approximately 10, 100, or 1000 times higher than a recited lower limit.

[0037] As will be understood by the skilled artisan, all numbers, including those expressing quantities, properties, purities, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired goals sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements. When values are expressed as approximations, by use of the antecedent "about," it will be understood that the value without the modifier "about" also forms a further aspect. The terms "about" and "approximately" are used interchangeably. Both terms can refer to a variation of ± 5%, ± 10%, ± 20%, or ± 25% of the value specified. For example, "about 50" percent can in some embodiments carry a variation from 45 to 55 percent, or as otherwise defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and / or less than a recited integer at each end of the range. Unless indicated otherwise herein, the terms "about" and "approximately" are intended to include values, e.g., weight percentages, proximate to the recited range that are equivalent in terms of the functionality of the individual ingredient, composition, or embodiment. The terms "about" and "approximately" can also modify the endpoints of a recited range as discussed above in this paragraph.

[0038] As will be understood by the skilled artisan, all numbers, including those expressing quantities, properties, reaction conditions, and so forth, are approximations and are understood as being optionally modified in all instances by the term "about." These values can vary depending upon the desired properties sought to be obtained by those skilled in the art utilizing the teachings of the descriptions herein. It is also understood that such values inherently contain variability necessarily resulting from the standard deviations found in their respective testing measurements.

[0039] As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges recited herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof, as well as the individual values making up the range, particularly integer values. A recited range (e.g., weight percentages) includes each specific value, integer, decimal, or identity within the range. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, or tenths. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art, all language, such as "up to", "at least", "greater than", "less than", "more than", "or more", and the like, include the number recited, and such terms refer to ranges that can be subsequently broken down into sub-ranges as discussed above. In the same manner, all ratios recited herein also include all sub-ratios falling within the broader ratio. Accordingly, specific values recited for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents.

[0040] One skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in a Markush group, the invention encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group. Additionally, for all purposes, the invention encompasses not only the main group, but also the main group absent one or more of the group members. The invention therefore envisages the explicit exclusion of any one or more of members of a recited group. Accordingly, provisos may apply to any of the disclosed categories or embodiments whereby any one or more of the recited elements, species, or embodiments, may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation.

[0041] The terms "contacting" or “applying” refer to the act of touching, making contact, or of bringing to immediate or close proximity, including at the cellular or molecular level, for example, to bring about a physiological reaction, a chemical reaction, or a physical change, e.g., on the skin of a human or animal, in an emulsion, in a solution, in a reaction mixture, in vitro, or in vivo.

[0042] An "effective amount" refers to an amount effective to bring about a recited effect, such as, an amount of an ingredient or a combination of ingredients necessary to form a product(s) in a reaction mixture, an amount of a composition necessary to bring about a therapeutic effect, or an amount of time necessary to apply a composition to bring about a therapeutic effect. Determination of an effective amount is typically within the capacity of persons skilled in the art, especially in light of the detailed disclosure provided herein. Thus, an "effective amount" generally means an amount that provides a desired effect.

[0043] The term "substantially" as used herein, is a broad term and is used in its ordinary sense, including, without limitation, being largely but not necessarily wholly that which is specified. For example, the term could refer to a numerical value that may not be 100% the full numerical value. The full numerical value may be less by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, or about 20%.

[0044] A “topical” product is one that may be administered to the cutaneous (skin) or other external body tissue surface (such as a mucous membrane) to treat a condition of the skin or other tissue to which the product is applied. Common formats for topical formulations include serums, ointments, lotions, creams, solutions, gels, and foams.

[0045] A "serum" is a highly concentrated product often used in the skincare industry (and other industries) to deliver active ingredients directly to the skin. Typically, serums have a thin, fastabsorbing consistency targeting specific concerns, such as, hydration, brightening, anti-aging, and acne. Serums generally contain fewer ingredients and focus on high concentrations of active ingredients to maximize efficacy.

[0046] “Dispersion” in chemistry is a mixture in which fine particles of one substance are scattered throughout another substance. The two phases may be in the same or different states of matter (e.g., gas, fluid, liquid, or solid). A dispersion can be classified as a suspension, colloid, or solution. Generally, the particles in a solution are of molecular or ionic size; those in a colloid are larger, but too small to be observed with an ordinary microscope; and those in a suspension can be observed under a microscope or with the naked eye. A coarse mixture (e.g., sand mixed with sugar) is usually not thought of as a dispersion.

[0047] The dispersion of fine particles in a liquid plays an important role in many processes of particle technology. Particles that are suspended in a liquid phase are referred to as solid / liquid dispersions. There are two general ways to produce a solid / liquid dispersion: (1) size reduction of the solid phase in a liquid to ensure uniformity, and (2) precipitation of fine particles in a liquid phase. Surfactants may be used to enhance the wettability of the solids in the liquid phase. Viscosity modifiers may be incorporated in the liquid phase to reduce sedimentation of the particles dispersed in the liquid phase.

[0048] As used herein, "precipitation" is the sedimentation of a solid material, a precipitate, from a liquid solution in which the material is present in amounts greater than its solubility in the liquid.

[0049] An “emulsion” can be defined as a colloid consisting of two or more non-homogenous type of liquids wherein one of the liquids contains a dispersion of the other liquid. Typical emulsions basically consist of a dispersion of two liquids that are immiscible with each other. One of the liquids acts as a continuous dispersion medium and the other acts as a dispersed phase. In other words, emulsions are colloids in which both the dispersed phase and continuous dispersion medium are liquids.

[0050] "Aqueous emulsions" contain water or an aqueous solution as one of the phases. In an oil-in- water emulsion, the oil forms droplets that disperse throughout the water medium. Conversely, a water- in-oil emulsion contains water droplets that disperse throughout the oil medium. A typical triple water and oil emulsion has water dispersed in oil droplets, which themselves are then dispersed in water, and is referred to as a water-in-oil-in-water emulsion (w / o / w), while the less common reverse analogue is termed oil-in-water-in-oil emulsion (o / w / o). The term emulsion may also be applied to a group of mixed systems, such as solutions, gels, or suspensions.

[0051] Emulsions, particularly micro-, mini-, and nano- emulsions, can be advantageous for topically delivering an active (and / or inactive) ingredient(s) into different layers of the epidermis and into systemic circulation of the body. Conventional topical treatments, such as gels and creams, generally have low efficiency, and poor cosmetic and aesthetic appeal, which can lead to poor patient compliance or adherence, while systemic and photo therapy often produce meaningful adverse side effects. The small particle and droplet sizes that are present in a nano-emulsion (-5-500 nm) formulation can enhance the appearance, delivery, and penetration of an active (and / or inactive) ingredient through the epidermis and layers of the skin.

[0052] The International Union of Pure and Applied Chemistry (IUPAC) defines an emulsion as a fluid system in which liquid droplets are dispersed in a continuous liquid medium. The droplets may be amorphous, liquid-crystalline, or any mixture thereof. The diameters of the droplets constituting the dispersed phase usually range from about 10 nm to about 100 pm; however, the droplets may exceed the usual size limits for colloidal particles. An emulsion is termed an oil / water (o / w) emulsion if the dispersed phase is an organic material (an ‘oil’) and the continuous phase is water or an aqueous solution. It is termed a water / oil (w / o) emulsion if the dispersed phase is water or an aqueous solution and the continuous phase is an organic material (an ‘oil’). As used herein, a "substantially or completely oil phase-free emulsion" is an emulsion that does not contain a continuous or dispersed oil phase or contains such a small amount of an oil phase (continuous or dispersed) that it does not materially affect the properties of the emulsion.

[0053] Emulsions contain both a continuous phase and a dispersed phase, with the boundary between the phases called the “interface”. Emulsions can have a cloudy appearance due to one or more phase interfaces scattering light passing through the emulsions. They can appear to have white color when the light is dispersed in equal proportions. If an emulsion is dilute, then higher-frequency and shorter- wavelength types of light will be scattered in more fractions, and vice-a-versa if the emulsion is more concentrated (lower-frequency and longer-wavelength types of light will be scattered in more fractions). For example, one kind of this type of an emulsion will appear blue in color (the “Tyndall effect”.) The Tyndall effect (or Tyndall scattering) is light scattering by particles in a colloid. Under the Tyndall effect, the longer wavelengths are transmitted more, while the shorter wavelengths are more diffusely reflected via scattering, so blue light is scattered much more strongly than red light.

[0054] Emulsions may be further defined by their particle size. While the following definitions of types of emulsion (i.e., macro-, micro-, nano-, and mini-) recite particles size ranges, it understood that the ranges are approximate.

[0055] The term “macro-emulsion” generally denotes a dispersion having a particle size of about 1-100 nm.

[0056] The term “micro-emulsion” (ME) came of widespread use in the 1950’s to describe a multiphase system consisting essentially of water, oil, surfactant, and alcohol. MEs are thermodynamically stable micellar colloidal dispersions having a particle size of about 10-100 nm. MEs can form a clear or transparent solution, usually with simple mixing of the ingredients. They are low-viscosity systems generally containing an aqueous phase, an oil phase, a surfactant, and a co-surfactant. MEs are a type of micellular dispersion that generally require a higher concentration of surfactant loads versus typical micellular solutions.

[0057] The term “nano-emulsion” (NE), which are sometimes called sub-micron emulsions (SME) and mini-emulsions, denotes a dispersion having a particle size ranging between about 20 and 200 nm. It also describes a multi-phase system that exhibits a clear or transparent colloidal dispersion. However, in contrast to a ME, a NE is usually thermodynamically unstable and requires high shear processing to form.

[0058] The term "mini-emulsion" (MiniE) denotes a dispersion having a particle size ranging between about 100 and 500 nm.

[0059] “Micelles” are an aggregate of molecules in a colloidal solution. In aqueous systems, they are organized structures formed by the surfactants in water. Clear micellular solutions in aqueous oil-in- water dispersions generally use surfactants and / or solvents to reduce the oil droplet size to < about 50 nanometers. This point is referred to as the critical micelle concentration (CMC). Above the CMC, these structures surround hydrophobic ingredients, like fragrances and oils, and can form clear or transparent dispersions if the right surfactants and / or solvents are used at high enough concentrations.

[0060] An “emulsifier” is a substance that stabilizes an emulsion by increasing its kinetic stability. Emulsifiers are a part of a broader group of compounds known as surfactants, or "surface-active agents". Surfactants (emulsifiers) are compounds that are typically amphiphilic, meaning they have a polar or hydrophilic (i.e., water-soluble) part and a non-polar (i.e., hydrophobic or lipophilic) part. Because of this dual modality, emulsifiers tend to have more or less solubility either in the water or oil phase. Emulsifiers that are more soluble in water (and conversely, less soluble in oil) will generally form oil-in-water emulsions, while emulsifiers that are more soluble in oil (and conversely, less soluble in water) will generally form water-in-oil emulsions.

[0061] “Miscibility” is the property of two substances to completely mix to form a homogeneous solution. Usually, the term is used to describe liquid mixtures, but can also be applied to solids and gases. Two substances are miscible if they mix in all proportions or concentrations to form a solution. In other words, it doesn’t matter whether you mix them equally or one component is present in a greater amount than the other. Two substances are immiscible if they don’t completely mix to form a solution. When combined, immiscible substances separate into layers or form a heterogeneous mixture. Miscibility is the capability of a mixture (for example, a mixture of two different liquids) to form a single phase over defined ranges of temperature, pressure, and composition. The existence of a single phase generally depends on the chemical structure, molar-mass distribution, and molecular architecture of the components present. If a mixture is thermodynamically metastable, it can de-mix if suitably nucleated. If a mixture is thermodynamically unstable, it can de-mix by spontaneous decomposition (i.e., without nucleation) or by nucleation and growth if suitably nucleated.

[0062] “Solubility” generally refers to the degree to which a substance dissolves in a solvent to make a solution (usually expressed as grams of solute per liter of solvent). Solubility of one fluid (liquid or gas) in another may be complete (totally miscible; e.g., methanol and water) or partial (e.g., oil and water dissolve only slightly). In general, “like dissolves like” (e.g., different aromatic hydrocarbons dissolve in one another, but not in water). Solubility is the ability of a solid, liquid, or gaseous chemical substance (referred to as the solute) to dissolve in a solvent (generally, a liquid) and form a solution. The solubility of a substance generally depends on the conditions and environment to which it is exposed, such as, the types of solvent used, their polarity, and the temperature and pressure to which they are subjected. The solubility of a substance in a particular solvent can be measured by the concentration of a saturated solution. A solution is considered saturated when adding additional solute no longer increases the concentration of the solution. The degree of solubility ranges widely depending on the substances, from infinitely soluble (fully miscible), such as ethanol in water, to poorly soluble, such as silver chloride in water. The term “insoluble” is often applied to poorly soluble compounds. Under certain conditions, the equilibrium solubility can be exceeded, yielding a supersaturated solution. Solubility does not depend on particle size; given enough time, even large particles will eventually dissolve.

[0063] “Poorly water-soluble chemical compounds” are described herein based on the United States Pharmacopeia (USP) guidelines. The USP designates the solubility of drugs as parts of solvent required for one part solute. The solubility of a drug comprising active and / or inactive ingredients may be expressed in several ways, such as by weight percentage, molarity, and molality. The USP lists the solubility of a drug as the quantity of milliliters of solvent in which 1g of solute will dissolve and assigns a descriptive term as shown in Table 1 provided below.

[0064] TABLE 1

[0065] USP solubility: Descriptive term Part of solvent required per part of solute Very soluble less than 1 Freely soluble from 1 to 10 Soluble from 10 to 30

[0066] Sparingly soluble from 30 to 100

[0067] Slightly soluble from 100 to 1000 Very slightly soluble from 1000 to 10,000 Practically insoluble 10,000 and over

[0068] The chemical compounds exemplified herein meet this criterion for slightly soluble, very slightly soluble, and practically insoluble, which are collectively defined as “poorly water-soluble” chemical compounds. Table 2 lists a number of representative poorly water-soluble chemical compounds to which the invention can be applied.

[0069] TABLE 2

[0070] Solubility table of representative compounds as they relate to the USP solubility definition. The term "di ethylene glycol monoethyl ether" ("DEGEE") refers to the compound 2-(2- ethoxyethoxy)ethanol. It is also known as 3,6-dioxa-l-octanol, 2-(2-ethoxyethoxy)ethanol, ethoxydiglycol, or by the trade name Transcutol®. It is a straight-chain organic compound with the formula C6H14O3: CH3CH2OCH2CH2OCH2CH2OH. It is a colorless and odorless liquid that is used as a solvent for a variety of commercial applications. DEGEE is miscible in water and often used as a cosolvent or carrier to enhance the solubility and permeability of chemical compounds when they are applied to the skin of a human or animal. It may be produced by the ethoxylation of ethanol, to wit, the condensation of ethylene oxide and ethanol, followed by distillation. The presence of both ether and alcohol functionalities in the molecule provide excellent solubilizing capacity. DEGEE is an odorless liquid that is used chiefly as a solubilizer and permeability enhancer for making a variety of products, including soaps, dyes, cosmetics (e.g., vitamin C, dihydroxyacetone (DHA) and benzoyl peroxide), and other chemicals. It has also been used in hair care products to promote a longer lasting and more uniform coloring. DEGEE is a pharmacological excipient that is widely used as a solubilizer in cosmetics as well as in oral, topical, transdermal, and injectable pharmaceutical formulations. There are limitations for its usage. DEGEE is most always used as a co-solvent and generally needs to be formulated to a concentration of less than about 50% (preferably, less than about 20%) in a topical formulation. For example, in the FDA Inactive Ingredient Database, there is an FDA approved topical product using 49% DEGEE. While DEGEE does not possess any oil or emulsification properties, it is a useful co-solvent for its miscibility properties with water and some oils, like almond oil or oleic acid.

[0071] The term "poly(ethylene glycol)" or "PEG" refers to the compound H(OCH2CH2)nOH, wherein n is usually 2 to about 1,000 in the PEG chain, or a derivative thereof. Several PEG compounds are commonly used as a synthetic emulsifying agent in a variety of products. Typically, the chain number (n) will be much greater than two segments, such as, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, about 600, or about 800 segments, or any range in between any of the aforementioned values. The molecular weight (in g / mol) of a PEG chain can be about 500 to about 200,000, about 500 to about 20,000, about 2,000 to about 15,000, about 3,500 to about 12,000, about 3,000 to about 9,000, about 4,000 to about 7,000, about 200 to about 40,000, about 300 to about 30,000, about 400 to about 20,000, about 5,000, about 6,000, about 8,000, about 10,000, about 12,000, about 15,000, about 20,000, about 25,000, about 30,000, or any range in between any of the aforementioned values.

[0072] The PEG group can be capped at its terminal end with a protecting group, such as an acetyl group or an alkyl group, for example, a methyl or an ethyl group. In a polymer, two or more ethylene glycol segments can form a poly(ethylene glycol) ("PEG") chain. The PEG groups can have single, double, or branched chains, and / or monocyclic or polycyclic rings. In certain circumstances, higher molecular weight PEG chains may be useful to increase the solubility of block copolymers in conjugating multiple types of water-insoluble drugs and / or molecules. "PEG 40 HCO" is a poly(ethylene glycol) (n = 40) hydrogenated derivative of castor oil. It is a waxy, viscous liquid emulsifier that is miscible in water. PEG-n HCO, where n equals 2 to about 1,000, is a common synthetic emulsifying agent found in a variety of products. Polyoxyl-n hydrogenated castor oil grades can serve as a multi-functional emulsifier, surfactant, foam booster, emollient, cleaning agent, solubilizer, thickener, carrier, permeability enhancer, and / or co-solvent. It can be found in many goods spanning various industries, such as pharmaceuticals, cosmetics, food products, skin care products, and personal care products. Many PEG-n HCO compounds (for example, where n = 30-40) do not possess oil properties. They do, however, possess unique emulsifying and solubilizing properties, and are soluble in both water and oil. Thus, these compounds are particularly useful in formulating aqueous formulations that contain a large water phase, and in combination with an oil or other type of fat or lipid, can prepare oil-in-water nano-emulsions that possess clear and stable oil droplets.

[0073] "Oleic acid" is a fatty acid that occurs naturally in various animal and vegetable fats and oils. It is classified as a monounsaturated omega-9 fatty acid. Oleic acid is used as a component in many foods, in the form of its triglycerides. It is a component of the normal human diet, being found in animal fats and vegetable oils. Oleic acid as its sodium salt is a major component of soap as an emulsifying agent. It is also used as an emollient. Small amounts of oleic acid are often used as an excipient in pharmaceuticals, or an emulsifying or solubilizing agent in aerosol products. Oleic acid is widely used in the solution phase synthesis of nano-particles, functioning as a kinetic knob to control the size and morphology of nanoparticles.

[0074] "Caprylic acid" is a medium (eight-carbon) straight-chain fatty acid, also known systematically as "octanoic acid". It is heptane in which one of the hydrogens of a terminal methyl group has been replaced by a carboxy group and is a conjugate acid of an octanoate. It is an oily liquid with a slightly unpleasant rancid-like smell found naturally in coconuts and breast milk and is minimally soluble in water. It has a role as an antibacterial agent and a human or Escherichia coli metabolite.

[0075] "Caprylate" is a salt or ester of caprylic acid (also known as octanoic acid (C8)).

[0076] "Glyceryl", also called glycerine or glycerin, is a simple triol compound. It is a natural compound derived from vegetable oils or animal fats. It is a clear, colorless, odorless, viscous, syrupy liquid that is sweet-tasting and non-toxic. It is a radical derived from glycerol by removal of hydroxide, especially, a trivalent radical CH2CHCH2. A glycerol backbone is found in lipids known as glycerides.

[0077] The term "polyglyceryl" refers to a polymer chain of glycerin molecules. The number of glyceryl molecules is denoted by "n", where n is > 1. It is possible to control not only how long the chain ends up but also where each glyceryl molecule joins on the chain.

[0078] A "polygly ceryl ester" is formed when you add a fatty acid (e.g., lauric, stearic, or oleic) to the polyglyceryl compound under alkaline conditions. This breaks enough of the internal bonds to enable the two chemicals to join up forming a new molecule that is now called an ester due to the type of bond created. The joining of water-loving glyceryl molecules with oil-loving fatty acid long tail molecules in a single compound provide advantageous properties that make these compounds useful as formulation emulsifiers. Modifying the fatty acid chain length and / or the polyglyceryl weight changes the emulsification power. Further, the vast quantity of glycerol functional groups makes these emulsifiers very moisturizing and mild to the skin.

[0079] Both glycerin and fatty acid can be sourced from animal fats or petroleum. It is more popular today to source them from plants, rather than synthetically. They are widely used in products for the cosmetic and personal hygiene industries. They are also used in the food industry for emulsifying bakery products, keeping chewing gum moist, and to replace some fats that are used in the cosmetics and pharmaceutical industry to help hold creams together, modify viscosity of emulsions, and disperse and solubilize fragrances and other active ingredients. Overall, they are highly regarded due to their mildness, flexibility, moisture holding capacity and biodegradability. They can also be produced sustainably from renewable resources.

[0080] "Glyceryl caprylate" is a monoester of glycerin and caprylic acid. The chemical formula of glyceryl caprylate is C11H22O4.

[0081] "Polyglyceryl-n caprylate" is a monoester of polyglycerin-n and caprylic acid, where "n" is >1. "Polyglyceryl- 10 caprylate" is a monoester of poly glycerin- 10 and caprylic acid.

[0082] Glyceryl caprylate and polyglyceryl-n caprylate are multi-functional ingredients commonly used in cosmetics and personal care formulations as a preservative, moisturizer, emollient, emulsifier, and cleansing agent. As a preservative, they help extend the shelflife of cosmetic products by inhibiting the growth of microorganisms. Additionally, they contribute to the texture and feel of formulations, acting as an emollient to soften and smooth the skin. Their mildness makes it suitable for sensitive skin. These compounds are often preferred by cosmetic and personal care manufacturers seeking alternatives to traditional synthetic preservatives due to their relatively natural origin and compatibility with various product types.

[0083] The term “dimethyl isosorbide” (“DMI”) refers to the compound 2,5-dimethyl isosorbide. It is also known as isosorbide dimethyl ether or (3R,3aR,6S,6aR)-3,6-dimethoxyhexahydrofuro[3,2-b]furan. DMI is the dimethyl ether of an anhydride of an isomer of sorbitol. It is a clear liquid that can function as a solvent, carrier (e.g., disperse pigments for color applications), and / or permeability enhancer. DMI is miscible in water and often used as a co-solvent to enhance the solubility and permeability of chemical compounds for topical application to the skin of a human or animal.

[0084] "Liposomes" are small artificial vesicles, spherical in shape, having at least one lipid bilayer. These sphere-shaped vesicles consisting of one or more phospholipid bilayers were first described in the 1960s. Today, they are a useful reagent and tool in various scientific disciplines, including mathematics, theoretical physics, biophysics, chemistry, colloid science, biochemistry, and biology. Due to their hydrophobicity and / or hydrophilicity, biocompatibility, particle size and other properties, liposomes can be used as drug delivery vehicles for administration of drugs and nutrients, such as lipid nanoparticles in mRNA and DNA vaccines. As a drug delivery system, liposomes characterize an advanced technology to deliver active molecules to the site of action. Today, liposomes are generally the most used nano-carriers for various potentially active hydrophobic and hydrophilic molecules due to their high biocompatibility, biodegradability, and low immunogenicity. They also prove to enhance drug solubility and controlled distribution, as well as have a capacity for surface modifications for targeted, prolonged, and sustained release. Based on the composition, liposomes can be considered to have evolved from conventional, long-circulating, targeted, and immune-liposomes to stimuli- responsive and actively targeted liposomes.

[0085] Description.

[0086] Liposomes are one of the most used nano-carriers for various potentially active hydrophobic and hydrophilic molecules due to their high biocompatibility, biodegradability, and low immunogenicity. Liposomes enhance drug solubility and controlled distribution, and have the capacity to produce surface modifications for targeted, prolonged, and sustained release. Liposomes are spherical lipid vesicles (usually 50-500 nm in diameter particle size) composed of one or more lipid bilayers, as a result of emulsifying natural or synthetic lipids in an aqueous medium.

[0087] Liposomes are one of the preeminent ways to topically deliver active ingredients into different layers of the epidermis and systemic circulation. Conventional topical treatments, such as gels and creams, provide low efficiency, and poor cosmetic and aesthetic appeal, which leads to poor patient compliance or adherence. Furthermore, systemic and photo therapy often produce significant adverse side effects. A liposomal emulsion is usually defined as an emulsion system consisting of an oil, a surfactant, and water to provide an isotropic, transparent (or translucent) appearance. A liposomal emulsion droplet size is generally defined as less than 200 nm. Nonetheless, if the emulsion has a low enough surfactant content, and is kinetically stable, a size of less than 500 nm is usually accepted as a liposome. Generally, the smaller the droplet size, the better the delivery and penetration of a chemical compound through the skin layers.

[0088] Since the inventive emulsions disclosed herein possess several liposomal characteristics, it is believed that the inventive emulsion compositions may be classified as liposomes or pseudo-liposomes.

[0089] Most emulsions usually contain particles and droplets having a mean diameter of greater than about 1pm. However, mini-, micro-, and nano- emulsions according to the invention can be designed with particle and droplet sizes in the range of about 100-500 nm. With proper formulation, highly stable emulsions can be prepared having particles and droplets as small as a few nanometers.

[0090] Oil-in water (o / w) and water-in-oil (w / o) emulsions comprising oil, water, surfactants (or other emulsifying agents), and co-solvents, have been the subject of many formulations to improve the look, delivery, and bioavailability of an active compound(s). DEGEE and PEG compounds have been used to make o / w emulsions with some of the compounds described herein.

[0091] The inventor of this disclosure has previously described a novel aqueous based emulsion composition containing a solvent system comprising DEGEE and a PEG compound for solubilizing poorly water-soluble chemical compounds without the substantial or complete presence of an oil phase in International Publication No. WO 2023 / 201042 (Menning), which is hereby incorporated by reference in its entirety. That publication disclosed an aqueous emulsion comprising: (i) about 2.5% to about 50% by weight of DEGEE; (ii) about 5% to about 20% by weight of a PEG compound; (iii) about 60% to about 92% by weight of water; and (iv) about 0.01% to about 2% by weight of a poorly water- soluble chemical compound dispersed in the emulsion. Unexpectedly, the aqueous emulsion was stable and transparent despite being substantially or completely devoid of an oil phase.

[0092] One object of the invention described herein was to discover a new composition comprising a co-solvent other than a PEG compound (e.g., PEG 40 HCO) to combine with DEGEE and form an aqueous based emulsion composition without the substantial or complete presence of an oil phase for solubilizing poorly water-soluble chemical compounds. This disclosure describes such a composition. The PEG compound can be replaced with a polyglyceryl-containing chemical compound (e.g., poly glyceryl- 10 caprylate), or a derivative thereof and form a similar type of emulsion composition.

[0093] Another object of the invention described herein was to discover a new composition comprising a co-solvent other than DEGEE to combine with a PEG compound (e.g., PEG 40 HCO) or a polyglyceryl-containing chemical compound (e.g., poly glyceryl- 10 caprylate) and form an aqueous based emulsion composition without the substantial or complete presence of an oil phase for solubilizing poorly water-soluble chemical compounds. This disclosure describes such a composition. DEGEE can be replaced with DMI or a derivative thereof and form a similar type of emulsion composition.

[0094] The emulsion compositions described herein can be used as a platform to formulate aqueous emulsion compositions that are substantially or completely devoid of an oil phase yet can solubilize poorly water-soluble active and inactive compounds. The formulations of the invention can be beneficial for treating a variety of skin disorders, as well as other types of diseases and ailments, and developing products in the cosmetic (e.g., skincare) and personal hygiene industries.

[0095] Quercetin and epigallocatechin gallate (EGCG) are active constituents of natural products that have been shown in the literature to reduce inflammatory markers and act as antibacterial agents for the treatment of acne. Both active ingredients have low oral bioavailability. Therefore, oral treatments with these active ingredients have not been feasible. Quercetin and EGCG, as well as other flavonoids, such as trans- resveratrol, fisetin, rutin, and dihydroquercetin, are poorly water-soluble chemical compounds. In a solubility screening panel evaluating emulsifiers and surfactants for use in topical delivery of poorly water-soluble chemical compounds, the compounds were found to be soluble in DEGEE. Similarly, DMI was evaluated and found to efficiently solubilize the poorly water-soluble chemical compounds.

[0096] The poorly water-soluble chemical compounds listed in the Definition section above require an enabling technology to deliver them to the skin of a human or animal in need of the compounds.

[0097] Emulsifiers from esters of fatty acids and polyglyceryl were screened for their ability to form liposomes as compared to PEG 40 HCO. A stock solution of active ingredients EGCG and quercetin dissolved in DEGEE was added to the required amount of the emulsifier. Water was then added to the mixture to evaluate the degree of precipitation. The concentrations (w / w) of the ingredients in the resulting formulations were about: 0.8% EGCG, 0.08% quercetin, 2.6% DEGEE, 7.5% emulsifier, and 89.02% purified water. PEG 40 HCO was used as a positive control. The absence of an emulsifier was used as a negative control. The results of the screening study are provided in Table 3.

[0098] TABLE 3

[0099] The results were surprising and unexpected for poly glyceryl- 10 caprylate performing as well as PEG 40 HCO. The emulsifiers listed in the table are known for their use in creating emulsions of oil and water. The formulations containing EGCG and quercetin dissolved in DEGEE with polyglyceryl- 10 caprylate or PEG 40 HCO were clear and substantially or completely lacked an oil phase. All the other emulsifiers performed as expected with the precipitation of EGCG and quercetin from the mixtures.

[0100] The art of formulating a topical composition for skincare products, or to treat a disease, ailment, or disorder through the skin, entails a sophisticated application of multiple scientific disciplines, e.g., chemistry, biology, physics, mathematics, and materials. A common challenge to a formulator is how best to mix an active ingredient(s) with other (active or inactive) ingredients to provide an efficacious and easy to use composition. It has been determined through experimentation that the substantially or completely oil phase-free aqueous emulsions of the invention can be used as a platform to solubilize poorly water-soluble active (as well as inactive) ingredients. The compositions and methods of use described herein can be helpful for producing a variety of products in multi-disciplinary areas.

[0101] The inventive aqueous emulsion compositions described herein substantially or completely lack an oil phase.

[0102] In an embodiment, the aqueous emulsion composition comprises a combination of:

[0103] (i) about 50% to about 92% by weight of water;

[0104] (ii) about 0.1% to about 50% by weight of DEGEE;

[0105] (iii) about 1% to about 30% by weight of poly glyceryl- 10 caprylate; and

[0106] (iv) about 0.01% to about 2% by weight of a poorly water-soluble chemical compound; wherein the water functions as a continuous aqueous dispersion medium and ingredients (ii), (iii), and (iv) function as a liquified dispersed phase in the aqueous emulsion that is substantially or completely devoid of an oil phase.

[0107] Ingredients (ii), (iii), and (iv) are not considered an oil phase with respect to the inventive aqueous emulsion composition.

[0108] In another embodiment, the aqueous emulsion comprises a combination of:

[0109] (i) about 50% to about 92% by weight of water;

[0110] (ii) about 0.1% to about 30% by weight of DMI;

[0111] (iii) about 1% to about 30% by weight of poly glyceryl- 10 caprylate or about 5% to about 20% by weight of a PEG compound; and

[0112] (iv) about 0.01% to about 2% by weight of a poorly water-soluble chemical compound; wherein the water functions as a continuous aqueous dispersion medium and ingredients (ii), (iii), and (iv) function as a liquified dispersed phase in the aqueous emulsion that substantially or completely lacks an oil phase.

[0113] The inventive emulsions described herein unexpectedly materially increase the solubility of the ingredients (e.g., poorly water-soluble ingredients) in the dispersed phase.

[0114] In an embodiment, n is about 30 to about 40 in the PEG compound (e.g., PEG 40 HCO).

[0115] In an embodiment, the substantially or completely oil phase-free aqueous emulsion may further comprise about 10% to about 49% by weight of a cleansing agent, a fragrance, an oil, and / or a thickening agent.

[0116] In an embodiment, the aqueous emulsion composition completely lacks an oil phase.

[0117] In an embodiment, the weight of the water comprises about 55% to about 90%, about 55% to about 85%, about 55% to about 80%, about 55% to about 75%, about 55% to about 70%, about 55% to about 65%, about 60% to about 90%, about 60% to about 85%, about 60% to about 80%, about 60% to about 75%, about 60% to about 70%, about 65% to about 90%, about 65% to about 85%, about 65% to about 80%, about 65% to about 75%, about 70% to about 90%, about 70% to about 85%, about 70% to about 80%, about 75% to about 90%, about 75% to about 85%, or about 80% to about 90%. In an embodiment, the weight of DEGEE comprises about 0.2% to about 40%, about 0.2% to about 30%, about 0.2% to about 20%, about 0.2% to about 10%, about 0.2% to about 5%, about 0.5% to about 40%, about 0.5% to about 30%, about 0.5% to about 20%, about 0.5% to about 10%, about 0.5% to about 5%, about 1% to about 40%, about 1% to about 30%, about 1% to about 20%, about 1% to about 10%, about 1% to about 5%, about 1.3% to about 40%, about 1.3% to about 30%, about 1.3% to about 20%, about 1.3% to about 10%, or about 1.3% to about 5%.

[0118] In an embodiment, the weight of poly glyceryl- 10 caprylate comprises about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 2% to about 7.5%, about 2% to about 5%, about 3.75 to about 30%, about 3.75% to about 25%, about 3.75% to about 20%, about 3.75% to about 15%, about 3.75% to about 10%, about 3.75% to about 7.5%, about 3.75% to about 5%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 1% to about 7.5%, about 7.5% to about 30%, about 7.5% to about 25%, about 7.5% to about 20%, about 7.5% to about 15%, about 7.5% to about 12%, about 7.5% to about 10%, about 10% to about 30%, about 9% to about 25%, about 9% to about 20%, about 9% to about 15%, or about 9% to about 12%.

[0119] In an embodiment, the DMI comprises about 2% to about 30%, about 2% to about 25%, about 2% to about 20%, about 2% to about 15%, about 2% to about 10%, about 2% to about 7.5%, about 2% to about 5%, about 3.75 to about 30%, about 3.75% to about 25%, about 3.75% to about 20%, about 3.75% to about 15%, about 3.75% to about 10%, about 3.75% to about 7.5%, about 3.75% to about 5%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 1% to about 7.5%, about 7.5% to about 30%, about 7.5% to about 25%, about 7.5% to about 20%, about 7.5% to about 15%, about 7.5% to about 12%, about 7.5% to about 10%, about 10% to about 30%, about 9% to about 25%, about 9% to about 20%, about 9% to about 15%, or about 9% to about 12%.

[0120] In an embodiment, the weight of the poorly water-soluble chemical compound comprises about 0.02% to about 2%, about 0.02% to about 1.5%, about 0.02% to about 1%, about 0.02% to about 0.5%, about 0.02% to about 0.3%, about 0.02% to about 0.1%, about 0.02% to about 0.05%, about 0.05% to about 2%, about 0.05% to about 1.5%, about 0.05% to about 1%, about 0.05% to about 0.5%, about 0.05% to about 0.3%, about 0.05% to about 0.1%, about 0.06% to about 2%, about 0.06% to about 1.5%, about 0.06% to about 1%, about 0.06% to about 0.5%, about 0.06% to about 0.3%, about 0.06% to about 0.1%, about 0.08% to about 2%, about 0.08% to about 1.5%, about 0.08% to about 1%, about 0.08% to about 0.5%, about 0.08% to about 0.3%, about 0.08% to about 0.1%. about 0.14% to about 2%, about 0.14% to about 1.5%, about 0.14% to about 1%, about 0.14% to about 0.5%, about 0.14% to about 0.3%, about 0.22% to about 2%, about 0.22% to about 1.5%, about 0.22% to about 1%, about 0.22% to about 0.5%, about 0.22% to about 0.3%, about 0.3% to about 2%, about 0.3% to about 1.5%, about 0.3% to about 1%, or about 0.3% to about 0.5%. In an embodiment, the weight of the cleansing agent, fragrance, oil, and / or thickening agent comprises about 15% to about 45%, about 15% to about 40%, about 15% to about 35%, about 15% to about 30%, about 15% to about 25%, about 15% to about 20%, about 20% to about 45%, about 20% to about 40%, about 20% to about 35%, about 20% to about 30%, about 20% to about 25%, about 25% to about 45%, about 25% to about 40%, about 25% to about 35%, about 25% to about 30%, about 30% to about 45%, about 30% to about 40%, about 30% to about 35%, about 35% to about 45%, about 35% to about 40%, or about 40% to about 45%.

[0121] The poly glyceryl- 10 caprylate-containing aqueous emulsion composition provides an optimized topical delivery system to deliver natural products, such as flavonoids (flavonols, flavanols, flavones, flavanones, isoflavones, and anthocyanins), without the need of an oil phase or a PEG compound. It further can be used as a formulation platform to form liposomes or pseudo-liposomes of flavonoids or other active and inactive ingredients. Formulations according to the invention provide an emulsion platform that can be useful for making products in many industries (e.g., pharmaceutical, cosmetic, personal care, industrial, food, etc.). In the pharmaceutical area, it can be used to make products that treat a variety of ailments and disorders, such as hair loss, psoriasis, cancer, inflammation, and pigmentary disorders (e.g., vitiligo and melasma). The compositions can also be designed to provide prophylactic benefits, such as, UV protection, anti-aging protection, and dietary supplements for preventing and / or treating a variety of medical issues. They can be used for products that treat psoriasis, cancer, inflammation, or encapsulation gene therapy products, such as, siRNA, cccDNA, mRNA, etc.

[0122] The solubilized emulsion compositions can be mixed into a lotion base, body wash, shampoo, serum, tincture, ointment, and other skincare formulations (e.g., facial cream or lotion) to enhance permeation and delivery of active ingredients. The compositions can be used to formulate a variety of products, such as, a hair growth promoter, an anti-acne cream, a body wash, and a shampoo. The compositions are particularly useful for the absorption of active ingredients that undergo high first pass metabolism during oral delivery or require other modes of delivery. The compositions solve solubility issues with poorly water-soluble compounds having low bioavailability by creating liposomes or pseudo-liposomes that can efficiently deliver products and medications topically to the skin of a human or animal in need thereof.

[0123] The invention can be formulated as a macro, mini-, micro-, or nano- aqueous emulsion. It can be used as a formulation platform to create a micro- or nano- emulsion of an active ingredient (e.g., a flavonoid) without the substantial or complete presence of an oil phase in the emulsion. The emulsion platform can generate formulations containing nano-particles (and nano-droplets) that improve the appearance of a product, and efficiently deliver active (and / or inactive) ingredients topically, while addressing solubility issues inherent with poorly water-soluble chemical compounds, which adversely affect their bioavailability. The formulation platform can be used to create compositions that maintain transparency and solubility upon further dilution with water without the need for an oil phase used in conventional macro-, mini-, nano- and micro- oil-in-water or water-in-oil emulsions. The formulation platform offers a wide range of applications for topical delivery of poorly water-soluble chemical compounds that cannot be effectively orally dosed. The solubilized compositions can be mixed into a base, such as a lotion or cream, to enhance permeation and delivery properties of the chemical compounds.

[0124] A micro-emulsion is generally considered to be thermodynamically stable, while a nanoemulsion is generally considered to be kinetically stable. The micro- and nano-emulsions described herein can be both thermodynamically and kinetically stable.

[0125] In embodiments, a topical composition of the invention comprising an active ingredient may further comprise an inactive ingredient, such as a co-solvent, co-emulsifier, cationic, ionic or non-ionic co-surfactant, stabilizer, thickener, anti-oxidant, conditioner, moisturizer, emollient, penetration enhancer, preservative, nutrient, fragrance, pigment, colorant, dispersion agent, anti-pruritic agent, antiperspirant, anti-psoriatic agent, anti-seborrheic agent, anti-aging agent, anti-wrinkle agent, skin lightening agent, depigmenting agent, vitamin, nutrient, aroma, preservative, stabilizer, or a combination thereof.

[0126] The composition may comprise one or more active ingredients. For example, the active ingredient can be a natural product, such as a flavonoid (e.g., flavanol or flavonol) or a polyphenol. Exemplary natural products include, but are not limited to, fisetin, / raw.s-resveratrol, a milk thistle extract comprising silymarin, quercetin, dihydroquercetin, curcumin (and / or turmeric), (-)-epigallocatechin-3 -gallate (EGCG), rutin, diosmin, an extract of Centipeda minima, imatinib, and imatinib mesylate. The active ingredient can be a hair growth promoter, or an antibiotic, antiseptic, antifungal, antibacterial, anti-inflammation, analgesic, antiviral, anesthetic, anti-cancer (e.g., imatinib or its mesylate salt) or anti-acne agent.

[0127] Optionally, the composition may comprise a natural or essential (or essence) oil. Natural oils have been studied and marketed for a variety of skin disorders and other ailments in the pharmaceutical, food, personal care, skin care and cosmetic fields. Some examples include coconut, almond, grapeseed, olive, sunflower seed, argan, rosehip see, jojoba, marula, tea tree, and safflower oils. Similarly, essential or essence oils have been the subject of a variety of studies in these fields. Examples of essential or essence oils include lavender, chamomile, sandalwood, clary sage, rosemary, frankincense, geranium, neroli, lemon, lemongrass, cinnamon, tea tree, peppermint, wintergreen, eucalyptus, patchouli, pomegranate, carrot seed, tangerine, ylang-ylang (cananga tree), rose, myrrh, and jojoba oils.

[0128] Though essential, essence, and natural oils are derived from plants, there are differences between the two classes. Essential and essence oils are distilled from the leaves, roots, bark, and other aromatic portions of a plant or botanical. The oils evaporate and have a concentrated aroma and are often used in aromatherapy. Hence, essential and essence oils are concentrated, hydrophobic liquids containing volatile aromatic compounds derived from plants / botanicals. Due to their high potency, essential and essence oils can cause irritation to the skin and are usually diluted with a carrier oil to alleviate this issue.

[0129] In contrast, natural oils are usually pressed from the fatty portions of a plant or botanical, such as the seeds, nuts, or kernels. Chemically, natural oils are triglycerides in which the glycerin is esterified with three fatty acids. They are the main constituent of vegetable oils and animal fats. Natural oils are generally gentler on the skin than essential and essence oils and generally do not require the addition of a carrier oil to use them.

[0130] In embodiments, a topical composition can be in the form of an ointment, a cream, an emulsion, a lotion, a paste, an unguent, a gel, a tincture, a sunscreen a spray, or other topical dosage form. The aqueous emulsions described herein may further comprise a cleansing agent, an emollient, or an aromatic chemical compound. Ointments, creams, lotions, and unguents according to the invention may further comprise a wax, alcohol, or a petroleum-based mollifying agent.

[0131] Gels according to the invention optionally comprise a vegetable oil, for example, of up to about 5% by weight of the total composition. Gels may further comprise water and / or a thickening agent. The thickening agent may be a natural polysaccharide, such as xanthan gum, carrageen, alginate, and / or cellulose gum.

[0132] Pastes according to the invention may optionally comprise aloe gel and / or beeswax.

[0133] Lotions according to the invention may optionally comprise cetyl alcohol, an emulsifier, a fragrance, glycerol, petroleum jelly, a dye, one or more preservatives and / or a stabilizing agent.

[0134] A sunscreen composition according to the invention may optionally comprise a UV-absorbing or barrier agent in an amount, for example, of between about 0.1% and about 10% by weight of the total composition. Exemplary UV-absorbing compounds include, but are not limited to, benzone compounds, glyceryl PABA, roxadimate, octocrylene, octyl methoxycinnamate, ethoxyethyl p- methoxycinnamate, homomenthyl salicylate, ethylhexyl salicylate, trolamine salicylate, ecamsule, ensulizole, bemotrizinol, and bisoctrizole. Exemplary UV-barrier compounds include, but are not limited to, zinc oxide and titanium dioxide.

[0135] The emulsion system of the invention may comprise an antibiotic, antiseptic, antifungal, analgesic, antiviral, and / or stabilizer agent. Some examples of these agents are listed below.

[0136] Antibiotic agents include, but are not limited to, ampicillin, bacampicillin, carbenicillin indanyl, mezlocillin, piperacillin, ticarcillin, amoxicillin-clavulanic acid, ampicillin-sulbactam, benzylpenicillin, cloxacillin, dicloxacillin, methicillin, oxacillin, penicillin G, penicillin V, piperacillin tazobactam, ticarcillin clavulanic acid, nafcillin, procaine penicillin, cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephradine, cefaclor, cefamandol, cefonicid, cefotetan, cefoxitin, cefprozil, ceftmetazole, cefuroxime, loracarbef cefdinir, ceftibuten, cefoperazone, cefixime, cefotaxime, cefpodoxime proxetil, ceftazidime, ceftizoxime, ceftriaxone, cefepime, azithromycin, clarithromycin, clindamycin, dirithromycin, erythromycin, lincomycin, troleandomycin, cinoxacin, ciprofloxacin, enoxacin, gatifloxacin, grepafloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, trovafloxacin, oxolinic acid, gemifloxacin, perfloxacin, imipenem-cilastatin, meropenem, and aztreonam. In an embodiment, the amount of an antibiotic in a topical composition can be from about 0.01% to about 5% by weight of the total composition.

[0137] Antiseptic agents include, but are not limited to, iodine, manuka honey, octenidine dihydrochloride, phenol, polyhexanide, sodium chloride, sodium hypochlorite, calcium hypochlorite, sodium bicarbonate, methyl paraben, benzoyl peroxide, and sodium dehydroacetate. In an embodiment, the amount of an antiseptic agent in the topical formulation can be from about 0.01% to about 5% by weight of the total composition.

[0138] Antifungal agents include, but are not limited to, amphotericin B, candicidin, fflipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenti conazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfm, butenafme, naftifme, terbinafme, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, and balsam of Peru. In an embodiment, the amount of an antifungal agent in the topical formulation can be from about 0.01% to about 5% by weight of the total composition.

[0139] Analgesic agents include, but are not limited to, methyl salicylate, codeine, morphine, methadone, pethidine, buprenorphine, hydromorphine, levorphanol, oxycodone, fentanyl, and a nonsteroidal anti-inflammatory drug. In an embodiment, the amount of an analgesic agent in a topical formulation can be from about 0.01% to about 5% by weight of the total composition.

[0140] Antiviral agents include, but are not limited to, acyclovir, famciclovir, penciclovir, valacyclovir, trifluridine, docosanol, amantadine, rimantadine, oseltamivir, and zanamivir. In an embodiment, the amount of an anti-viral agent in a topical formulation can be from about 0.01% to about 5% by weight of the total composition.

[0141] Stabilizer agents include, but are not limited to, guar gum, xanthan gum cellulose hyaluronic acid, polyvinyl pyrrolidone (PVP), alginate, chondroitin sulfate, poly gamma glutamic acid, gelatin, chitosan, com starch, and flour. In an embodiment, the amount of a stabilizer agent in a topical formulation can be from about 0.25% to about 2% (w / v).

[0142] Formulations may be prepared by conventional procedures known in the pharmaceutical, cosmetic, skin care, personal care, food, and industrial chemical fields. It can be appreciated that the compositions described herein may be varied according to well-known techniques to accommodate differing amounts and types of ingredients. Additionally, the specific ingredients and proportions described herein are for illustrative purposes. Ingredients may be exchanged for suitable equivalents or substitutes, and proportions may be varied, according to the desired properties of the dosage form of interest.

[0143] Many active and inactive ingredients are characterized by low solubility in water and high solubility in oil or lipid mixtures. In topical applications, they do not easily adhere to or remain on the skin and have limited penetration properties. Some ingredients cannot be taken orally (due to ineffectiveness, toxicity issues or other adverse side effects). Given these limitations, it is challenging for a formulator to find the best (active and inactive) ingredients, and the best loading requirements, to enhance the efficacy of the ingredients in the composition when it is taken orally by or applied topically to the skin of a human or an animal. Similar limitations need to be addressed in other dosage formats (ocular, mucosal, intravenous, intramuscular, sublingual, etc.)

[0144] A skilled artisan in the field of topical formulations can utilize the compositions and methods described herein to create a high-quality effective product. The compositions according to the invention may be applied to any part of the skin, such as the face, scalp, back and other parts of the body. Once in contact with the skin, the inventive compositions can effectively and efficiently deliver an active and / or inactive ingredient and provide its beneficial attributes to a human or animal in need thereof.

[0145] The invention includes a method for personal care, hygiene, treating skin disorders, and treating other types of ailments by applying a therapeutically effective amount of the inventive compositions for a therapeutically effective amount of time to the skin of a human or an animal in need of the personal care, hygiene or treatment. When the composition comes in contact with the skin, an active ingredient contained therein can provide personal care or hygiene, or treat or ameliorate a variety of skin disorders and other types of diseases and ailments (e.g., systematic inflammation).

[0146] The DEGEE / poly glyceryl- 10 caprylate-containing inventive aqueous emulsion compositions described herein can be used to formulate products for all the uses described in WO 2023 / 201042 (Menning) for the DEGEE / PEG compound-containing aqueous emulsion composition - hair growth, wart removal, acne, alopecia areata, atopic dermatitis (eczema), psoriasis, Raynaud’s phenomenon, rosacea, skin cancer, vitiligo, melasma, and varicose or spider veins. Similarly, the DMI / polyglyceryl- 10 caprylate-containing and DMI / PEG derivative of castor oil-containing inventive aqueous emulsion compositions described herein can also be used for all the above indications.

[0147] Emulsion technology has been applied to numerous active molecules, including fisetin, transresveratrol and silymarin (from milk thistle extract). Fisetin, trans-resveratrol, and silymarin are active constituents of natural products that have been the subject of numerous studies accessing their hepatoprotective, antioxidant, anti-inflammatory, immunomodulatory, anti-cancer, cardioprotective, and hair growth properties. However, the studies have shown that all three compounds possess low oral bioavailability, thus limiting their effectiveness. Consequently, the three active compounds have not been successfully dosed orally and various formulations have been developed to topically deliver them to the body. Several studies have shown that some of the compounds can be topically delivered, predominantly using oil-in-water emulsion technology.

[0148] Fisetin (3,3',4',7-tetrahydroxyflavone) (2-(3,4-dihydroxyphenyl)-3,7-dihydroxy-4H-l- benzopyran-4-one) is a bioactive flavonol (flavonoid group of polyphenols) molecule found in many plants, fruits and vegetables, such as strawberry, apple, persimmon, grape, onion, and cucumber at concentrations in the range of about 2-160 pg / g. It has been suggested that fisetin possesses antiproliferative, apoptotic, and / or antioxidant activities. Papers have reported that fisetin may be an effective chemo-preventive / chemotherapeutic agent in several types of cancer and may have neuroprotective properties. However, fisetin has also been reported to have low oral bioavailability, likely due to its poor aqueous solubility (10.45 mcg / mL) and high lipophilicity (logP 3.2). Additionally, fisetin has been shown to be highly metabolized when taken orally or intravenously.

[0149] Resveratrol (5-[(E)-2-(4-hydroxyphenyl)ethen-l-yl]benzene-l,3-diol) is a natural polyphenolic stilbenoid found in a variety of plants, including many food items, such as blueberries, mulberries, raspberries, grapes, red wine, and peanuts. It exists as two isomers, namely, cis- and trans- resveratrol. The trans isomer has been reported as the more biologically active compound. Classified as a phytoalexin, trans- resveratrol can be produced in response to a fungal attack or the onset of certain types of stress, including trauma and UV irradiation. Trans-resveratrol has been examined for its potential therapeutic benefit in the treatment or prevention of cancer, heart disease, neurodegeneration, and inflammation. Trans-resveratrol is generally produced by isolating it from extracts of red wine / grape skin or from the plant Polygonum cuspidatum. However, it has low oral bioavailability, and its utility as a therapeutic in humans has been limited. The bioavailability of trans- resveratrol is about 0.5%, likely due to extensive hepatic glucuronidation and sulfation. The viability of an oral delivery method with / ran.s-resveratrol is questionable due to its low aqueous solubility and short half-life (about 15 min).

[0150] Silymarin is a flavonolignan extracted from the milk thistle Silybum marianum (L.) gaemt plant. It is composed of an isomeric mixture of seven flavonolignans - silybin A, silybin B isosilybin A, isosilybin B, silychristin A, silychristin B, and silydianin - and one flavonoid - taxifolin. Silybin, also known as silibinin, has the IUPAC chemical name of (2T?,3T?)-3,5,7-trihydroxy- 2-[(2T?,3T?)-3-(4- hydroxy-3-methoxyphenyl)-2-(hydroxymethyl) -2,3-dihydrobenzo[b][l,4]dioxin-6-yl]chroman-4-one. Silymarin has been shown to possess various pharmacological properties, like hepatoprotective, antioxidant, anti-inflammatory, anti-cancer, anti-fibrotic, and cardioprotective activities. Although clinical trials have shown silymarin to be non-toxic in humans at high doses (> about 1500 mg / day), pharmacokinetic studies have revealed poor absorption, rapid metabolism, and ultimately, poor oral bioavailability of the molecule.

[0151] There are many cases of oil-in-water macro, mini-, micro-, and nano- emulsions in the literature. See e.g., US Patent Nos. 10,918,606 and 10,736,842, and US Patent Publication Nos. 2021 / 0330598, 2021 / 077396, 2021 / 0046087, and 2018 / 0071390, which are hereby incorporated by reference in their entirety. Oil-in-water emulsions have been studied with fisetin, trans-resveratrol and silymarin, as well as other active chemical compounds, such as quercetin or dihydroquercetin (a flavonoid in the same class of compounds as fisetin, silymarin, and silibinin), carvediol, nitrendipine, vinpocetine, curcumin, (-)-epigallocatechin-3 -gallate (a polyphenol abbreviated as EGCG), and salicylic acid.

[0152] Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-l-benzopyran-4-one) and dihydroquercetin are plant pigment flavonoids (flavonols). They are potent antioxidants found in many plants and foods, such as red wine, onions, asparagus, broccoli, buckwheat, green tea, grapes, apples, cherries, berries, and citrus fruits. Quercetin has been reported to possess protective abilities against tissue injury induced by various drug toxi cities and exhibit antioxidant, anti-inflammatory, antibacterial, and anti-viral properties that might help reduce swelling, kill cancer cells, control blood sugar, and help prevent heart disease. It has been used as a prophylactic for oxidative stress diseases (cardiovascular, bronchopulmonary, etc.). Dihydroquercetin has been reported to be more potent and bioavailable than quercetin.

[0153] Curcumin (l,7-bis(4-hydroxy-3-methoxyphenyl)-l,6-heptadiene-3, 5-dione) is a plant-derived polyphenolic carotenoid compound. It is naturally present in the rhizome of the yellow root plant Curcuma longa (tumeric) and other Curcuma spp. It has been the subject of intensive investigations on account of its various activities (e.g., anti-inflammatory, anti-cancer, etc.) and can be found in numerous oral herbal supplements. Curcumin may help in the management of exercise-induced inflammation and muscle soreness, thus enhancing recovery and performance in active people. Dosing curcumin orally generally does not lead to the associated health benefits due to its poor bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination. Essential Turmeric Oil (ETO) coated curcumin has been shown to have about 7 to 10-fold higher bioavailability and be retained longer in systemic circulation, compared with standard curcumin.

[0154] (-)-Epigallocatechin-3 -gallate ([(27?,37?)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3- yl] 3, 4, 5 -trihydroxybenzoate) (EGCG,) is an ester of epigallocatechin and gallic acid. EGCG is a polyphenol (flavonoid) and is a type of catechin. It is the most abundant catechin in green tea. It has been studied for its potential to affect human health and diseases due to its antibacterial, antiviral, and anti-cancer properties. However, when taken orally, EGCG has poor absorption even at daily intakes equivalent to about 8-16 cups of green tea. After consumption, EGCG blood levels usually peak within 1.7 hours. The absorbed plasma half-life is about 5 hours, but a majority of unchanged EGCG is excreted into the urine from almost immediately to about 8 hours after consumption.

[0155] Salicylic acid (2 -hydroxybenzoic acid) belongs to a class of drugs known as salicylates. When applied to the skin, salicylic acid may work by helping the skin to shed dead cells from the top layer and by decreasing redness and swelling (inflammation). This application can decrease skin disorders, such as acne and warts, and speed the healing of the skin by ramping up the body’s immune system.

[0156] Rutin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(25,3R,45,55,6R)-3,4,5-trihydroxy-6- [[(2R,3R,4R,5R,65)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one), also known as rutoside, quercetin-3-rutinoside, and sophorin, is the glycoside combining the flavonol quercetin and the disaccharide rutinose. It is a flavonoid found in a wide variety of plants, fruits, and vegetables (e.g., the citrus flavonoid glycoside found in buckwheat). Rutin may have antioxidant and anti-inflammatory effects. It has been studied as a potential prophylactic against cancer and other diseases. Rutin is commonly used for autism, aging skin, airway infections caused by exercise, and other purposes, but there is little scientific evidence to support its effectiveness.

[0157] Centipeda minima (Kshavak / Sneezewort) is a plant leaf herb that has been used in Chinese medicine to treat respiratory diseases for centuries. Twelve common components, including flavones and their glycosides, phenolic and polyphenolic acids, and sesquiterpene lactone have been identified in an ethanol extract of Centipeda minima. Brevilin A is a sesquiterpene lactone isolated from Centipeda minima that has been shown to inhibit Janus kinase 3 (JAK3), which is a cellular pathway implicated in hair loss and cancer treatment.

[0158] Diosmin(5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[(25,3R,45,55,6R)-3,4,5-trihydroxy-6- [[(2R,3R,4R,5R,65)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one) is a disaccharide derivative that consists of diosmetin substituted by a 6-O-(alpha-L-rhamnopyranosyl)- beta-D-glucopyranosyl moiety at position 7 via a glycosidic linkage. It has a role as an antioxidant and an anti-inflammatory agent. It is a glycosyloxyflavone, a rutinoside, a disaccharide derivative, a monomethoxyflavone and a dihydroxyflavanone. It is functionally related to diosmetin.

[0159] Imatinib (4-[(4-methylpiperazin-l-yl)methyl]-A-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2- yl] amino }phenyl)benzami de) and its mesylate salt are 2-phenyl amino pyrimidine derivatives that function as specific inhibitors of a number of tyrosine kinase enzymes. They are small molecule inhibitors targeting multiple receptor tyrosine kinases such as CSF1R, ABL, c-KIT, FLT3, and PDGFR- P. Imatinib mesylate is commercially available under the brand names Gleevec® and Glivec®, among others, and is used as an oral targeted therapy medication to treat cancer.

[0160] The molecular structures of fisetin, / raw.s-resveratrol, silymarin, quercetin, curcumin, (-)-epigallocatechin-3 -gallate, salicylic acid, rutin, diosmin, imatinib, and imatinib mesylate are shown in Schemes 1-3 of WO 2023 / 201042 (Menning). All these compounds can be formulated using the inventive emulsion compositions described herein.

[0161] The new formulations described herein comprise a poorly water-soluble chemical compound with a solvent system comprising: (i) DEGEE and poly glyceryl- 10 caprylate or a derivative thereof; (ii) DMI and poly glyceryl- 10 caprylate or a derivative thereof; and (iii) DMI and a PEG compound (e.g., PEG 40 HCO). The poorly water-soluble chemical compounds dissolved in the inventive solvent systems are dispersed in a continuous aqueous based emulsion medium that substantially or completely lacks an oil phase. The compositions of the invention are useful for topical and other modes of application to care for skin and hair or treat various skin and hair disorders (e.g., hair loss, plantar warts, cold sores, etc.), as well as other types of diseases or ailments. The formulations of the invention maintain transparency and solubility upon further dilution with water without the need of a traditional oil phase required by, for example, nano- or micro- emulsion technology.

[0162] The platform has a wide range of applications for poorly water-soluble compounds.

[0163] While the description and examples focus on topical applications of the inventive emulsion containing a poorly water-soluble active ingredient(s), it can be readily realized that the invention can serve as a platform for formulating and delivering poorly water-soluble active and / or inactive ingredient(s) via modes other than topical, such as ocular, mucosal, intravenous, intramuscular, sublingual, and oral applications.

[0164] The following Examples are intended to illustrate the invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest other ways in which the invention could be practiced. It should be understood that numerous variations and modifications may be made while remaining within the scope of the invention.

[0165] EXAMPLES

[0166] All percentages listed for an ingredient in the following examples are an approximate weight percent of the total weight of the resulting composition.

[0167] Example 1. EGCG / Quercetin / DEGEE and Polyglyceryl Esters

[0168] A screening experiment was conducted to test polyglyceryl esters for the formation of an aqueous emulsion without the substantial or complete presence of an oil phase for EGCG and quercetin dissolved in DEGEE.

[0169] Method.

[0170] A DEGEE, EGCG, and quercetin stock solution was prepared by dissolving about 0.600g EGCG and about 0.063g quercetin in about 1.952g DEGEE. The mixture was added to a lOmL vial with the required amount of the solubilizing agent and stirred to create a uniform mixture with a magnetic stir bar. Water was then stirred into the mixture. Table 4 shows 10 different samples. TABLE 4

[0171] Results.

[0172] Sample 7 (7.5% PEG 40 HCO) was used as positive control and formed a clear solution with the addition of water.

[0173] Sample 8 (no solubilizer) was used as a negative control and formed a suspension with the addition of water.

[0174] Sample 1 (7.5% polyglycery-10 caprylate) initially formed a clear solution after the addition of water (like Sample 7), but precipitation occurred after 1 week of storage. However, it is believed that the subsequent precipitation of the formulation can be prevented by adjusting the loads of the other ingredients in the formulation or using different active ingredients.

[0175] Sample 2 (7.5% polyglyceryl-3 caprylate) precipitated after the addition of water.

[0176] Sample 3 (7.5% poly glyceryl- 10 laurate) formed a stable cloudy macro-emulsion after the addition of water.

[0177] Sample 4 (7.5% polyglyceryl-4 laurate) formed a gel layer and precipitated after the addition of water.

[0178] Sample 5 (7.5% poly glyceryl- 10 oleate) precipitated after the addition of water.

[0179] Sample 6 (7.5% polyglyceryl-4 oleate) precipitated after the addition of water.

[0180] Samples 9 and 10 (10% and 12% polyglycery-10 caprylate) formed a clear solution similar to Sample 7 after the addition of water. Both remained stable and clear after several months.

[0181] It can be concluded that aqueous emulsion compositions having concentrations of polyglyceryl- 10 caprylate greater than or equal to about 10% perform similarly to aqueous emulsions having concentrations of PEG 40 HCO greater than or equal to about 7.5% for EGCG and quercetin dissolved in DEGEE. It is further postulated that concentrations of poly glyceryl- 10 caprylate around 7.5% can also be used to form long term stable clear solutions with different loads of EGCG / quercetin / DEGEE or different active ingredients. Example 2. EGCG / Quercetin / DEGEE and Mixtures of Polyglyceryl Esters Mixtures

[0182] Another screening experiment was performed using solubilizing mixtures of polyglyceryl esters as listed below. Table 5 lists six different samples.

[0183] TABLE 5

[0184] Method.

[0185] The DEGEE, EGCG, quercetin stock solution of Example 1 was used in this experiment. All experiments were conducted at ambient temperature conditions. The stock solution was added to a 10 mL vial with the required amount of solubilizing agent (10%) and stirred to create a uniform mixture with a magnetic stir bar. Water was then stirred into the mixture. Table 6 lists the formulation concentrations of the six different samples.

[0186] TABLE 6

[0187] Results.

[0188] Only Sample G (10% PEG 40 HCO) formed a stable, clear solution that was stable for months after water addition. Samples D (10% TEGO® Solve 61) and E (10% Olivem® 2090) were cloudy and precipitated out after the addition of water.

[0189] Sample F (10% Caprylyl / Capryl Glycol) formed a dark orange solution indicating possible chemical incompatibility.

[0190] Samples H (10% Super Solv) and I (10% Poly Suga®Mulse D9) formed a clear solution after water addition but precipitated out after approximately 3 hours of storage.

[0191] Example 3. Body Wash

[0192] A formulation was prepared to evaluate the creation of liposomes in a body wash. The flavonoids rutin, / raw.s-resveratrol and fisetin were dissolved with stirring in DEGEE at about 0.1% of each flavonoid to about 1.3% DEGEE. Poly glyceryl- 10 caprylate was added at about 3.75% of the total formulation and mixing was applied to form a uniform mixture. Water was then stirred into the mixture at about 60.52% of the total formulation to create a clear, stable yellow-orange solution. Additional cleansing surfactants, oils, fragrances, and thickening agents were added to make up the remaining about 34.13% of the formulation. No precipitation was observed.

[0193] The final formulation comprises:

[0194] (i) about 60.52% by weight of water;

[0195] (ii) about 1.3% by weight of DEGEE;

[0196] (iii) about 3.75% by weight of polyglyceryl-10 caprylate;

[0197] (iv) about 0.1% by weight of each of rutin, trans- resveratrol and fisetin; and

[0198] (v) about 34.13% by weight of cleansing surfactants, oils, fragrances, and thickening agents; wherein ingredients (ii), (iii), (iv), and (v) are dispersed in a continuous aqueous emulsion medium.

[0199] Example 4. Shampoo

[0200] Another formulation was prepared to evaluate the creation of liposomes or pseudo-liposomes in a shampoo. The flavonoids trans- resveratrol and dihydroquercetin were dissolved with stirring in DEGEE at about 0.1% and about 0.05%, respectively, to about 1.3% DEGEE. Polyglyceryl-10 caprylate was added at about 3.75% of the total formulation and mixing was applied to form a uniform mixture. Water was then stirred into the mixture at about 71.68% of the total formulation to create a clear, stable yellow-orange solution. Additional cleansing surfactants, oils, fragrances, and thickening agents were added to make up the remaining about 23.12% of the formulation. No precipitation was observed.

[0201] The final formulation comprises:

[0202] (i) about 71.68% by weight of water;

[0203] (ii) about 1.3% by weight of DEGEE;

[0204] (iii) about 3.75% by weight of polyglyceryl-10 caprylate;

[0205] (iv) about 0.1% by weight of each of trans- resveratrol and dihydroquercetin; and

[0206] (v) about 23.12% by weight of cleansing surfactants, oils, fragrances, and thickening agents; wherein ingredients (ii), (iii), (iv), and (v) are dispersed in a continuous aqueous emulsion medium. Example 5. Quercetin, dimethyl isosorbide (DMI) and Polyglyceryl- 10 caprylate

[0207] A formulation was prepared to evaluate DMI as a solvent to dissolve quercetin and other flavonoids with poly glyceryl- 10 caprylate. Quercetin was dissolved with stirring in DMI at about 0.08% to about 2.6% DMI. Poly glyceryl- 10 caprylate was added at about 10% of the total formulation and mixing was applied to form a uniform mixture. Water was then stirred into the mixture at about 87.32% of the total formulation to create a clear, stable pale-yellow solution. No precipitation was observed.

[0208] Example 6. Quercetin, dimethyl isosorbide (DMI) and PEG 40 Hydrogenated Castor Oil (PEG 40 HCO)

[0209] A formulation was prepared to evaluate DMI as a solvent to dissolve quercetin and other flavonoids with PEG 40 HCO. Quercetin was dissolved with stirring in DMI at about 0.08% to about 2.6% DMI. PEG 40 HCO was added at about 7.5% of the total formulation and mixing was applied to form a uniform mixture. Water was then stirred into the mixture at about 89.82% of the total formulation to create a clear, stable pale-yellow solution. No precipitation was observed.

[0210] Example 7. Serum with Quercetin, EGCG, dimethyl isosorbide (DMI) and Poly glyceryl- 10 caprylate

[0211] A formulation was prepared to evaluate DMI as a solvent to dissolve quercetin and epigallocatechin gallate (EGCG). Quercetin and EGCG were dissolved with stirring in DMI at about 0.08% quercetin and about 0.8% EGCG to about 2.6% DMI. Poly glyceryl- 10 caprylate was added at about 10% of the total formulation and mixing was applied to form a uniform mixture. Water was then stirred into the mixture at about 85.12% of the total formulation to create a clear, stable pale-yellow solution. Preservatives and thickening agents were added to make up the remaining about 1.4% of the formulation. No precipitation was observed.

[0212] The final formulation comprises:

[0213] (i) about 85.12% by weight of water;

[0214] (ii) about 2.6% by weight of DMI;

[0215] (iii) about 10% by weight of poly glyceryl- 10 caprylate;

[0216] (iv) about 0.08% by weight of quercetin and 0.8% by weight of EGCG dispersed in the aqueous emulsion; and

[0217] (v) about 1.4% by weight of preservatives and thickening agents; wherein ingredients (ii), (iii), (iv), and (v) are dispersed in a continuous aqueous emulsion medium. Example 8. Serum with Quercetin, EGCG, dimethyl isosorbide (DMI) and PEG 40 Hydrogenated Castor Oil (PEG 40 HCO)

[0218] A formulation was prepared to evaluate DMI as a solvent to dissolve quercetin and EGCG. Quercetin and EGCG were dissolved with stirring in DMI at about 0.08% quercetin and about 0.8% EGCG to about 2.6% DMI. PEG 40 HCO was added at about 7.5% of the total formulation and mixing was applied to form a uniform mixture. Water was then stirred into the mixture at about 87.62% of the total formulation to create a clear, stable pale-yellow solution. Preservatives and thickening agents were added to make up the remaining about 1.4% of the formulation. No precipitation was observed.

[0219] The final formulation comprises:

[0220] (i) about 87.62% by weight of water;

[0221] (ii) about 2.6% by weight of DMI;

[0222] (iii) about 7.5% by weight of PEG 40 HCO;

[0223] (iv) about 0.08% by weight of quercetin and 0.8% by weight of EGCG dispersed in the aqueous emulsion; and

[0224] (v) about 1.4% by weight of preservatives and thickening agents; wherein ingredients (ii), (iii), (iv), and (v) are dispersed in a continuous aqueous emulsion medium.

[0225] Example 9. Body Wash with Quercetin, EGCG, dimethyl isosorbide (DMI) and Poly glyceryl- 10 caprylate

[0226] A formulation was prepared to evaluate DMI as a solvent to dissolve quercetin and epigallocatechin gallate (EGCG). Quercetin and EGCG were dissolved with stirring in DMI at about 0.08% quercetin and about 0.8% EGCG to about 2.6% DMI. Poly glyceryl- 10 caprylate was added at about 10% of the total formulation and mixing was applied to form a uniform mixture. Water was then stirred into the mixture at about 74.92% of the total formulation to create a clear, stable pale-yellow solution. Cleansing surfactants, preservatives, and thickening agents were added to make up the remaining about 1.4% of the formulation. No precipitation was observed.

[0227] The final formulation comprises:

[0228] (i) about 74.92% by weight of water;

[0229] (ii) about 2.6% by weight of DMI;

[0230] (iii) about 10% by weight of poly glyceryl- 10 caprylate;

[0231] (iv) about 0.08% by weight of quercetin and 0.8% by weight of EGCG dispersed in the aqueous emulsion; and

[0232] (v) about 11.6% by weight of cleansing surfactants, preservatives, and thickening agents; wherein ingredients (ii), (iii), (iv), and (v) are dispersed in a continuous aqueous emulsion medium.

[0233] Example 10. Body Wash with Quercetin, EGCG, dimethyl isosorbide (DMI) and PEG 40 Hydrogenated Castor Oil (PEG 40 HCO)

[0234] A formulation was prepared to evaluate DMI as a solvent to dissolve quercetin and EGCG. Quercetin and EGCG were dissolved with stirring in DMI at about 0.08% quercetin and about 0.8% EGCG to about 2.6% DMI. Poly glyceryl- 10 caprylate was added at about 10% of the total formulation and mixing was applied to form a uniform mixture. PEG 40 HCO was added at about 7.5% of the total formulation and mixing was applied to form a uniform mixture. Water was then stirred into the mixture at about 77.42% of the total formulation to create a clear, stable pale-yellow solution. Cleansing surfactants, preservatives, and thickening agents were added to make up the remaining about 11.6% of the formulation. No precipitation was observed.

[0235] The final formulation comprises:

[0236] (i) about 77.42% by weight of water;

[0237] (ii) about 2.6% by weight of DMI;

[0238] (iii) about 7.5% by weight of PEG 40 HCO;

[0239] (iv) about 0.08% by weight of quercetin and 0.8% by weight of EGCG dispersed in the aqueous emulsion; and

[0240] (v) about 11.6% by weight of cleansing surfactants, preservatives, and thickening agents; wherein ingredients (ii), (iii), (iv), and (v) are dispersed in a continuous aqueous emulsion medium.

[0241] All publications, patents, and patent documents cited herein are incorporated by reference as though individually incorporated by reference. No limitations inconsistent with this disclosure are to be understood therefrom. The invention has been described with reference to various specific and preferred embodiments and techniques. However, variations and modifications may be made while remaining within the spirit and scope of the invention.

[0242] While specific embodiments have been described above with reference to the disclosed embodiments and examples, such embodiments are only illustrative and do not limit the scope of the invention. Changes and modifications can be made in accordance with ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

Claims

What is claimed is:

1. An aqueous emulsion that substantially or completely lacks an oil phase, the aqueous emulsion comprising a combination of:(i) about 50% to about 92% by weight of water;(ii) about 0.1% to about 50% by weight of di ethylene glycol monoethyl ether (DEGEE);(iii) about 1% to about 30% by weight of poly glyceryl- 10 caprylate; and(iv) about 0.01% to about 2% by weight of a poorly water-soluble chemical compound; wherein the water functions as a continuous aqueous dispersion medium and ingredients (ii), (iii), and (iv) function as a liquified dispersed phase in the aqueous emulsion that substantially or completely lacks an oil phase.2 The aqueous emulsion of Claim 1, wherein the poorly water-soluble chemical compound comprises fisetin, / raws- resveratrol, a milk thistle extract comprising silymarin, quercetin, dihydroquercetin, curcumin, turmeric, (-)-epigallocatechin-3 -gallate (EGCG), rutin, salicylic acid, diosmin, imatinib, imatinib mesylate, an extract of Centipeda minima, or a mixture thereof.3 The aqueous emulsion of Claim 2, wherein the poorly water-soluble chemical compound comprises:(i) fisetin, / raws- resveratrol, a milk thistle extract comprising silymarin, and / or rutin;(ii) / raws- resveratrol, EGCG, quercetin and / or dihydroquercetin;(iii) fisetin, / raws- resveratrol, rutin, and / or diosmin; or(iv) salicylic acid.4 The aqueous emulsion of Claim 1, further comprising about 10% to about 49% by weight of a cleansing agent, a fragrance, an oil, a thickening agent, or a mixture thereof.5 The aqueous emulsion of Claim 1, comprising nano-particles having a d50 particle size and a number weighted mean particle size each of less than about 150 nm.6 The aqueous emulsion of Claim 1, which is formulated to be administered to a human or animal in need thereof, topically, ocularly, mucosally, intravenously, intramuscularly, or orally.7 The aqueous emulsion of Claim 6, which is formulated for topical administration.

8. The aqueous emulsion of Claim 7, which is formulated as a skincare product.

9. The aqueous emulsion of Claim 8, wherein the skincare product comprises a body wash or a shampoo.

10. A method of cleaning or treating a body of or hairs on a human or animal in need thereof, the method comprising topically applying a therapeutically effective amount of the substantially or completely oil phase-free aqueous emulsion of Claim 1 for a therapeutically effective time to the body of or the hairs on the human or animal, wherein the chemical compound comprises fisetin, / raws- resveratrol, a milk thistle extract comprising silymarin, quercetin, dihydroquercetin, curcumin, turmeric, (-)-epigallocatechin-3 -gallate (EGCG), rutin, salicylic acid, diosmin, imatinib, imatinib mesylate, an extract of Centipeda minima, or a mixture thereof.

11. An aqueous emulsion that substantially or completely lacks an oil phase, the aqueous emulsion comprising a combination of:(i) about 50% to about 92% by weight of water;(ii) about 0.1% to about 30% by weight of dimethyl isosorbide (DMI);(iii) about 1% to about 30% by weight of poly glyceryl- 10 caprylate or about 5% to about 20% by weight of a polyethylene glycol (PEG: H(OCH2CH2)nOH) derivative of castor oil, wherein n is 2 to about 1,000; and(iv) about 0.01% to about 2% by weight of a poorly water-soluble chemical compound; wherein the water functions as a continuous aqueous dispersion medium and ingredients (ii), (iii), and (iv) function as a liquified dispersed phase in the aqueous emulsion that substantially or completely lacks an oil phase.

12. The aqueous emulsion of Claim 11, wherein the poorly water-soluble chemical compound comprises fisetin, / raws- resveratrol, a milk thistle extract comprising silymarin, quercetin, dihydroquercetin, curcumin, turmeric, (-)-epigallocatechin-3 -gallate (EGCG), rutin, salicylic acid, diosmin, imatinib, imatinib mesylate, an extract of Centipeda minima, or a mixture thereof.

13. The aqueous emulsion of Claim 12, wherein the poorly water-soluble chemical compound comprises:(i) fisetin, trans- resveratrol, a milk thistle extract comprising silymarin, and / or rutin;(ii) trans- resveratrol, EGCG, quercetin and / or dihydroquercetin;(iii) fisetin, trans- resveratrol, rutin, and / or diosmin; or(iv) salicylic acid.

14. The aqueous emulsion of Claim 11, further comprising about 10% to about 49% by weight of a cleansing agent, a fragrance, an oil, and / or a thickening agent.

15. The aqueous emulsion of Claim 11, comprising nano-particles having a d50 particle size and a number weighted mean particle size each of less than about 150 nm.

16. The aqueous emulsion of Claim 11, which is formulated to be administered to a human or animal in need thereof, topically, ocularly, mucosally, intravenously, intramuscularly, or orally.

17. The aqueous emulsion of Claim 16, which is formulated for topical administration.

18. The aqueous emulsion of Claim 17, which is formulated as a skincare product.

19. The aqueous emulsion of Claim 18, wherein the skincare product comprises a body wash or a shampoo.

20. A method of cleaning or treating a body of or hairs on a human or animal in need thereof, the method comprising topically applying a therapeutically effective amount of the substantially or completely oil phase-free aqueous emulsion of Claim 11 for a therapeutically effective time to the body of or the hairs on the human or animal, wherein the poorly water-soluble chemical compound comprises fisetin, / raws- resveratrol, a milk thistle extract comprising silymarin, quercetin, dihydroquercetin, curcumin, turmeric, (-)-epigallocatechin-3 -gallate (EGCG), rutin, salicylic acid, diosmin, imatinib, imatinib mesylate, an extract of Centipeda minima, or a mixture thereof.

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