Emulsion formulations of compounds with low water solubility

Abstract

Aqueous emulsion systems that are substantially or completely devoid of an oil phase. Aqueous emulsions can be used as a platform to solubilize chemical compounds that are poorly water-soluble for use in a variety of fields, such as pharmaceuticals, cosmetics, skin care, personal care, food, and industrial fields. Aqueous emulsions can be delivered to humans or animals via a variety of modes to treat a variety of ailments, such as topical compositions to promote hair growth or treat skin disorders. Stable and transparent formulations of aqueous nanoemulsions described herein can be used to treat and / or prevent hair loss, treat warts and cold sores, or treat varicose veins.

Description

[Technical field]

[0001] Related Applications This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 331,628, filed April 15, 2022, which is incorporated by reference herein. [Background technology]

[0002] Emulsions are used in a wide variety of industrial, cosmetic, personal care, skin care and pharmaceutical products, including ophthalmic, topical, mucosal, intravenous, intramuscular, sublingual and oral products. Emulsions are also used as precursors for preparing polymeric microparticles, solid lipid nanoparticles, inorganic nanoparticles and oil-filled microcapsules, and have been developed as precursors for magnetic particles for imaging, diagnostics and drug delivery. Despite their widespread use, they remain an underutilized pharmaceutical format.

[0003] It can be difficult to incorporate poorly water-soluble chemical compounds into aqueous systems. 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 mix an oil phase with a water phase in combination with an emulsifier to form an emulsion colloid. This type of emulsion colloid has an oil phase, a water phase, and a surfactant or other emulsifier, and may also contain a co-solvent that helps solubilize the poorly water-soluble chemical compounds.

[0004] Oil and water are immiscible liquids that do not form a homogeneous mixture when added together. However, when mixed with an emulsifier, they can form emulsions (e.g., oil-in-water, water-in-oil, or water-in-oil-in-water triple emulsions) in which chemical compounds with low water solubility (but oil soluble) can be dispersed. Emulsions are thermodynamically stable isotropic systems in which two immiscible liquids (e.g., oil and water) are mixed and a monodispersion is formed by an emulsifier (e.g., surfactant + cosurfactant). One of the immiscible liquids is dispersed in the form of very small globules (internal phase) throughout the other immiscible liquid (external phase). The resulting emulsion is a kinetically stable, clear (i.e., transparent or translucent) dispersion of two immiscible phases. Even if the liquids that form them are clear, emulsions can be cloudy or colored because light is scattered by the particles suspended in the mixture.

[0005] Chemical compounds with low water solubility may adversely affect the appearance and efficacy of the compound in a product. Active chemical compounds with low water solubility show reduced bioavailability in products (such as pharmaceuticals, cosmetics, or foods), especially in products with high water concentrations. Some active compounds cannot be administered orally because they are not effective or may cause harm (e.g., due to fast metabolism due to short half-life, toxicity issues, side effects, etc.). Oil-in-water and water-in-oil emulsions, including oil, water, surfactants (or other emulsifiers), and cosolvents, have been formulated and studied with active ingredients that are low in water solubility. These studies have demonstrated the general need to have an oil phase in compositions to form aqueous-based emulsion systems that include one or more different types of low water solubility active and inactive compounds.

[0006] Although various kinds of formulations have been developed, their effectiveness and side effects are not desirable.There is a demand for better formulations that effectively deliver active and inactive chemical compounds with low water solubility to humans or animals.There remains a need for improved formulations that contain active and inactive chemical compounds with low water solubility.There is a need for new aqueous-based topical compositions that contain active and inactive chemical compounds with low water solubility.

[0007] The approach described in this patent seeks to meet these demands by providing a novel aqueous-based emulsion system that is substantially or completely free of an oil phase. The emulsion system described herein can be used as a platform for formulating oil-free aqueous compositions containing poorly water-soluble active and inactive compounds that may be beneficial in treating various skin disorders and other types of diseases and ailments. Summary of the Invention

[0008] Described herein are aqueous emulsion systems substantially or completely absent of an oil phase that include a combination of the following: (i) about 2.5% to about 50% by weight of diethylene glycol monoethyl ether (DEGEE); (ii) about 5% by weight to about 20% by weight of polyethylene glycol (PEG:H(OCH 2 CH 2 ) n OH) derivatives, where n is from 2 to about 1,000; (iii) about 60% to about 92% by weight of water; and (iv) From about 0.05% by weight to about 2.0% by weight of a poorly water-soluble chemical compound dispersed in a substantially or completely oil-free emulsion.

[0009] Emulsion systems can act as a platform for delivering poorly water-soluble chemical compounds in a variety of ways, for example, orally, sublingually, topically, or by injection, and are particularly useful for topical dermatological (skin) therapeutic applications.

[0010] In some embodiments, n is equal to about 30 to about 40 in the PEG chain of the polyethylene glycol derivative of castor oil. In certain embodiments, the polyethylene glycol derivative of castor oil is PEG 40 hydrogenated castor oil (PEG 40 HCO).

[0011] The oil-free aqueous composition can be a mini-, micro- or nano-emulsion. The nano-emulsion can have a d50 nanoparticle size and a number weighted average nanoparticle size of less than about 150 nm, respectively. The particle size and droplet size can be reduced or increased by optimizing the loading of the material components in the composition. The illustrated embodiment has a d50 nanoparticle size and a number weighted average nanoparticle size of less than about 50 nm, respectively.

[0012] Oil-free aqueous emulsions can be conveniently used to solubilize active and inactive ingredients that are poorly water-soluble. In one embodiment, the active ingredient can be a natural product, such as a flavonoid (e.g., flavanol) or a polyphenol. The oil-free aqueous emulsions containing one or more of the following different natural products are exemplified below: fisetin, trans-resveratrol, milk thistle extract containing silymarin, quercetin (or dihydroquercetin), (-)-epigallocatechin-3-gallate (EGCG), salicylic acid, gossypium, curcumin (or turmeric), rutin, diosmin, and imatinib or imatinib mesylate. These natural products have been the subject of much research into their potential uses, including the treatment and prevention of alopecia.

[0013] In one embodiment, a hair growth composition was prepared comprising: (i) about 2.5% by weight to about 20% by weight of DEGEE; (ii) about 5% to about 10% by weight PEG 40 HCO; (iii) about 60% to about 92% by weight of water; and (iv) Active chemical compounds with poor water solubility, including: (a) about 0.075% to about 0.250% by weight of fisetin; (b) about 0.075% to about 0.150% by weight of trans-resveratrol; and / or (c) about 0.125% to about 0.250% by weight, of a milk thistle extract containing about 0.1% to about 0.2% by weight of silymarin.

[0014] The invention further includes application methods that may be beneficial for treating various skin disorders. The examples show various topical applications. Two exemplary skin disorders that can be effectively treated with the formulations described herein are alopecia and human papilloma virus (HPV) warts by topically applying a therapeutically effective amount of the formulation with the required active ingredient to the affected area of ​​the skin disorder in a human or animal in need thereof for a therapeutically effective amount of time. The emulsion system can be used as a platform to create formulations with various poorly water-soluble chemical compounds, such as natural and synthetic active and inactive compounds. The emulsions can be employed for non-topical applications (e.g., intraocular, mucosal, intravenous, intramuscular, and oral products). Depending on the active ingredient(s) selected, the emulsions can be used to treat many diseases (e.g., psoriasis, cancer, inflammation, pigmentation disorders such as vitiligo and melasma) other than those exemplified herein.

[0015] The invention further includes a method for formulating an oil-free aqueous emulsion.

[0016] The above and other objects and features of the disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying drawings. Further embodiments, forms, features, aspects, benefits, objectives, and advantages of the invention will become apparent from the detailed description and the drawings provided accompanying herewith.

[0017] The following drawings form part of the specification and are included to further explain certain embodiments or various aspects of the invention. In some cases, embodiments of the invention can be best understood by referring to the accompanying drawings in combination with the detailed description presented herein. The description and accompanying drawings may emphasize certain specific examples or certain aspects of the invention. However, one skilled in the art will understand that parts of the embodiments or aspects may be used in combination with other embodiments or aspects of the invention. Features, objects, and advantages will be more readily apparent in light of the following detailed description. The detailed description refers to the following drawings. [Brief description of the drawings]

[0018] [Figure 1] Photographs of a male human scalp (after haircut) are shown (a) before and (b) after 4 weeks of treatment with a nanoemulsion formulation containing fisetin. [Diagram 2] Photographs of the left foot of a human male with a wart mass are shown before (a) and after (b) four weeks of treatment with a nanoemulsion formulation containing (-)-epigallocatechin-3-gallate (EGCG) and quercetin. [Diagram 3] Photographs of the right foot of a human male with two wart lumps are shown (a) before and (b) after four weeks of treatment with a nanoemulsion formulation containing (-)-epigallocatechin-3-gallate (EGCG) and quercetin. [Figure 4] (a) Photograph showing removal of a wart mass on the foot of a human male, and (b) a pictorial representation of the virus and roots in the wart mass.

[0019] The present invention is susceptible to various modifications and alternative forms, and exemplary embodiments thereof are shown by way of example in the drawings and are described in detail herein. However, it should be understood that the description of exemplary embodiments is not intended to limit the invention to the specific types disclosed. On the contrary, it is intended to cover all modifications, equivalents and alternatives that are within the spirit and scope of the invention as defined by the embodiments herein and the claims below. To interpret the scope of the invention, reference should be made to the embodiments and the claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] The novel oil-free aqueous emulsion system described herein can be used as a platform for solubilizing active and inactive ingredients that are poorly water soluble. Below are definitions for some of the terms used in this disclosure.

[0021] definition In order to provide a clear and consistent understanding of the specification and claims, the following definitions are included. In this specification, the recited terms have the following meanings. All other terms and phrases used in this specification have their ordinary meanings as understood by those skilled in the art. Such ordinary meanings can be obtained by referring to specialized dictionaries, such as Hawley's Condensed Chemical Dictionary, 14th Edition, RJ Lewis, John Wiley & Sons, New York, NY, 2001.

[0022] References in the specification to "one embodiment," "an embodiment," and the like indicate that the embodiment being described may include a particular aspect, property, structure, moiety, or feature, but not all embodiments necessarily include that aspect, property, structure, moiety, or feature. Moreover, such phrases may, but do not necessarily, refer to the same embodiment that is referenced in other parts of the specification. Furthermore, when a particular aspect, property, structure, moiety, or feature is described in the context of one embodiment, it is within the knowledge of one of ordinary skill in the art to affect or connect such aspect, property, structure, moiety, or feature with other embodiments, whether or not explicitly described.

[0023] The singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to "a compound" includes a plurality of such compounds, and thus, compound X includes a plurality of compound 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 a precondition for the use of exclusive terminology, such as "only," "only," and the like in connection with any element described herein, and / or the use of a recitation or "negative" limitation of the claim elements.

[0024] The term "and / or" means any one of the items, any combination of the items, or all of the items with which the term is associated. The phrase "one or more" is readily understood by one of ordinary skill in the art, particularly when read in the context of its use. For example, the phrase can mean 1, 2, 3, 4, 5, 6, 10, 100, or any upper limit that is approximately 10, 100, or 1000 times higher than the recited lower limit.

[0025] As will be appreciated by those of skill in the art, all numbers, including those expressing amounts, properties, purity, reaction conditions, and the like, are approximate and are understood to be optionally modified in all instances by the term "about." These values ​​may vary depending on the desired objective sought to be obtained by the skilled artisan using the teachings set forth herein. It is also understood that such values ​​inherently contain variability necessarily resulting from the standard deviation 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.

[0026] The terms "about" and "approximately" are used interchangeably. Both terms can indicate a variation of ±5%, ±10%, ±20%, or ±25% of the specified value. For example, "about 50" percent can have a variation of 45-55 percent in some embodiments, or may be otherwise defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and / or less than the recited integers at each end of the range. Unless otherwise stated herein, the terms "about" and "approximately" are intended to include the nearest value, e.g., weight percentage, to the recited range that is equivalent in terms of the functionality of the individual material components, compositions, or embodiments. The terms "about" and "approximately" can also modify the endpoints of the recited ranges described above in this paragraph.

[0027] As will be understood by one of ordinary skill in the art, all numbers, including those expressing amounts, properties, reaction conditions, and the like, are approximate and are understood to be optionally modified in all instances by the term "about." These values ​​may vary depending upon the desired properties sought to be obtained by the skilled artisan utilizing the teachings set forth herein. It is also understood that such values ​​inherently contain variability necessarily resulting from the standard deviation found in their respective testing measurements.

[0028] As will be understood by those skilled in the art, for all purposes, particularly in terms of providing a written specification, all ranges recited herein also encompass any and all possible subranges and combinations of subranges, as well as the individual values, particularly integer values, that make up the range. A recited range (e.g., percentages by weight) includes each specific value, integer, decimal, or identity within the range. Any recited range is fully described and can be readily recognized as allowing the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths. As a non-limiting example, each range described herein can be readily broken down into a lower third, a middle third, and an upper third, etc. As will be understood by those skilled in the art, all language, such as "up to," "at least," "greater than," "less than," "greater than," "greater than," etc., includes the recited numbers, and such terms indicate a range that can be subsequently broken down into the subranges described above. In the same manner, all ratios recited herein also include all sub-ratios within that broader ratio. Thus, specific values ​​recited for radicals, substituents, and ranges are for illustration only; they do not exclude other stated values ​​or other values ​​that are within the stated ranges for the radicals and substituents.

[0029] Those skilled in the art will also readily recognize that when members are grouped together in a common manner, for example, in a Markush group, the invention encompasses not only the entire group recited as a whole, but also each member of the group individually, and all possible subgroups of the main group. In addition, for all purposes, the invention encompasses not only the main group, but also the main group without one or more group members. As such, the invention envisions the explicit exclusion of one or more members of any of the recited groups. Thus, where a proviso is applicable to any of the disclosed categories or embodiments, any one or more recited elements, species, or embodiments may be excluded from such categories or embodiments, for example, for use in an explicit negative limitation.

[0030] The terms "contact" or "applying" refer to the act of touching, bringing into contact, or bringing into immediate or close proximity, including at the cellular or molecular level, such that a physiological response, chemical reaction, or physical change is elicited, for example, on the skin of a human or animal, in an emulsion, in a solution, in a reaction mixture, in vitro, or in vivo.

[0031] "Effective amount" refers to an amount effective to cause a recited effect, such as the amount of ingredients or combination of ingredients required to form a product(s) in a reaction mixture, the amount of a composition required to cause a therapeutic effect, or the amount of time required to apply a composition to cause a therapeutic effect. Determination of an effective amount is typically within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Thus, "effective amount" generally refers to an amount that provides a desired effect.

[0032] The term "substantially" is used herein as a broad term and in its ordinary sense, including, but not limited to, a majority, but not necessarily all, of what is specified. For example, the term could indicate a numerical value that may not be 100% the entire numerical value. The entire numerical value may be less than 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%.

[0033] A "topical" pharmaceutical is one that is administered to the skin or other external tissue surface (e.g., mucous membrane) to treat a condition of the skin or other tissue to which the pharmaceutical is applied. Common formats for topical formulations include ointments, lotions, creams, solutions, gels, and foams.

[0034] A "dispersion" in chemistry is a mixture in which tiny particles of one substance are scattered throughout another. The two phases may be of the same or different states of matter (e.g., gas, fluid, liquid, or solid). Dispersions can be classified as suspensions, colloids, or solutions. Generally, the particles in a solution are of molecular or ionic size; the particles in a colloid are larger but too small to be seen with a regular microscope; the particles in a suspension can be seen under a microscope or with the naked eye. Coarse mixtures (e.g., sand mixed with sugar) are not usually considered dispersions.

[0035] Dispersions of fine particles in liquids play an important role in many powder engineering processes. Particles suspended in a liquid phase are called solid / liquid dispersions. There are two general methods to generate solid / liquid dispersions: (1) size reduction of the solid phase in the liquid to ensure homogeneity, and (2) precipitation of fine particles in the liquid phase. Surfactants can be used to enhance the wetting of the solid in the liquid phase. Viscosity modifiers can be incorporated into the liquid phase to reduce settling of particles dispersed in the liquid phase.

[0036] As used herein, "precipitation" is the settling of a solid material, a precipitate, from a liquid solution where the material is present in an amount that exceeds its solubility in that liquid.

[0037] An "emulsion" can be defined as a colloid composed of two or more non-homogeneous types of liquids, where one of the liquids contains a dispersion of the other liquid. An emulsion is essentially composed of a dispersion of two liquids that are immiscible with each other. One of the liquids acts as the dispersion medium and the other acts as the dispersed phase. In other words, an emulsion is a colloid in which both the dispersed phase and the dispersion medium are liquids. In an oil-in-water emulsion, the oil forms small droplets that are dispersed throughout the water. The term emulsion can also be applied to a group of mixed systems, such as solutions, gels, or suspensions.

[0038] The International Union of Pure and Applied Chemistry (IUPAC) defines an emulsion as a fluid system in which droplets are dispersed in a liquid. The droplets may be amorphous, liquid crystalline, or any mixture thereof. The diameter of the droplets that make up the dispersed phase is usually in the range of approximately 10 nm to 100 μm; that is, the droplets may exceed the usual size limit of colloidal particles. An emulsion is called an oil / water (o / w) emulsion when the dispersed phase is an organic material ("oil") and the continuous phase is water or an aqueous solution. When the dispersed phase is water or an aqueous solution and the continuous phase is an organic material ("oil"), it is called a water / oil (w / o) emulsion.

[0039] A substantially or completely "oil-free" emulsion is an emulsion that contains no continuous or dispersed oil phase, or that contains such a small amount of oil phase (continuous or dispersed) that it does not substantially affect the properties of the emulsion.

[0040] Emulsions contain both a continuous and a dispersed phase, and the boundaries between the phases are called "interfaces." Emulsions may have a cloudy appearance due to the many phase interfaces that scatter the light passing through the emulsion. If the light is dispersed in equal proportions, they may appear to have a white color. If the emulsion is dilute, a greater proportion of the high frequency and low wavelength types of light are scattered. For example, one type of emulsion of this type appears blue (the "Tyndall effect").

[0041] The term "microemulsions" (MEs) originates from its widespread use in the 1950s to describe multiphase systems composed essentially of water, oil, surfactant, and alcohol. MEs are thermodynamically stable micellar colloidal dispersions with particle sizes of about 10-100 nm. MEs are usually capable of forming clear or transparent solutions upon simple mixing of the material components. They are low viscosity systems containing an aqueous phase, an oil phase, a surfactant, and a co-surfactant. MEs are a type of micellar dispersion that generally requires a higher surfactant loading relative to a typical micellar solution.

[0042] The term "nanoemulsion" (NE) also refers to a clear or transparent colloidal dispersion. However, in contrast to MEs, NEs are not thermodynamically stable and often require high shear processing to form.

[0043] "Micelles" are aggregates of molecules in colloidal solutions. In aqueous systems, they are organized structures formed by surfactants in water. Clear micellar solutions of aqueous oil-in-water dispersions generally use surfactants and / or solvents to reduce the oil droplet size to < about 50 nanometers. This point is called the Critical Micelle Concentration (CMC). Above the CMC, these structures can surround hydrophobic ingredients such as fragrances and oils to form clear or transparent dispersions if the appropriate surfactants and / or solvents are used in high enough concentrations.

[0044] An "emulsifier" is a substance that stabilizes an emulsion by increasing its kinetic stability. Emulsifiers are part of a broader group of compounds known as surfactants, or "surface active agents." Surfactants (emulsifiers) are compounds that are typically amphiphilic, meaning that they have a polar or hydrophilic (i.e., water-soluble) portion and a non-polar (i.e., hydrophobic or lipophilic) portion. Because of this dual aspect, emulsifiers tend to have greater or lesser solubility in either water or oil. 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 form water-in-oil emulsions.

[0045] "Miscibility" is the property of two substances to mix completely and form a homogeneous solution. Usually the term is used to describe liquid mixtures, but it can also be applied to solids and gases. Two substances are miscible if they mix in all proportions or concentrations and form a solution. In other words, it does not matter if they are mixed equally or if one component is present in a greater amount than the other. Two substances are immiscible if they do not mix completely and form a solution. When combined, immiscible substances separate into layers or form a heterogeneous mixture. Miscibility is the ability of a mixture (e.g., a mixture of two different liquids) to form a single phase over a defined range of temperatures, pressures, and compositions. The existence of a single phase depends on the chemical structure, molar mass distribution, and molecular structure of the components present. If the mixture is thermodynamically metastable, it may demix once properly nucleated. If the mixture is thermodynamically unstable, it may demix by spontaneous decomposition (ie, without nucleation) or, if properly nucleated, by nucleation and growth.

[0046] "Solubility" generally refers to the degree to which a substance dissolves in a solvent and forms a solution (usually expressed as grams of solute per liter of solvent). The solubility of one fluid (liquid or gas) in another can be complete (totally miscible; e.g., methanol and water) or partial (e.g., oil and water are only slightly soluble). In general, "like dissolves like" (e.g., aromatic hydrocarbons dissolve in each other but not in water). Solubility is the ability of a solid, liquid, or gaseous chemical (called a solute) to dissolve in a solvent (usually a liquid) and form a solution. The solubility of a substance depends on the type of solvent used, their polarity, and the temperature and pressure to which they are subjected. The solubility of a substance in a particular solvent is measured by the concentration of the saturated solution. A solution is considered saturated when the concentration of the solution no longer increases with the addition of additional solute. Solubility can range widely for a substance, from infinitely soluble (completely miscible), e.g., ethanol in water, to sparingly soluble, e.g., silver chloride in water. The term "insoluble" is often applied to compounds that are poorly soluble. Under certain conditions, the equilibrium solubility can be exceeded, resulting in a supersaturated solution. Solubility is not dependent on particle size; given enough time, even large particles will eventually dissolve.

[0047] "Poorly Water-Soluble Chemical Compounds": The United States Pharmacopeia (USP) specifies the solubility of drugs as parts of solvent required for one part solute. The solubility of drugs, including active and / or inactive ingredients, can be expressed in many ways, for example, by weight percentage, molar concentration, and molality. The USP lists the solubility of drugs as the amount of milliliters of solvent in which 1 g of solute will dissolve, and are assigned descriptive terms in the summary provided below. [Table 1]

[0048] The chemical compounds employed in the examples below met the criteria for being slightly soluble, very slightly soluble, and practically insoluble, and are collectively defined as "poorly water soluble" chemical compounds. [Table 2]

[0049] The term "poly(ethylene glycol)" or "PEG" refers to the compound H(OCH 2 CH 2 ) n OH, where n is 2 to about 1,000 in the PEG chain, or a derivative thereof. In various embodiments, the molecular weight of the PEG chain can be about 500 to about 200,000. In certain embodiments, the PEG group can have a molecular weight of about 500 to about 20,000; about 2,000 to about 15,000; about 3,500 to about 12,000; or about 3,000 to about 9,000. In other embodiments, the PEG group can have a molecular weight of about 4,000 or about 7,000. The PEG group can be capped at its terminus with a protecting group, e.g., an acetyl group or an alkyl group, e.g., a methyl or ethyl group. In the polymer, two or more ethylene glycol segments can form a poly(ethylene glycol) ("PEG") chain. Typically, the number (n) is much greater than two segments, e.g., about 5, about 10, about 20, about 50, about 100, about 200, about 300, about 400, about 500, about 600, or about 800 segments, or any range between any two of the preceding values. In certain embodiments, n is about 30 to about 40. In an exemplary embodiment, n is 40.

[0050] The PEG chains can have a molecular weight of about 200 to about 40,000 g / mol. Some embodiments can have a PEG moiety of about 300 to about 30,000 g / mol, or about 400 to about 20,000 g / mol. Some embodiments can have a PEG moiety with a molecular weight of about 5,000, about 6,000, about 8,000, about 10,000, about 12,000, about 15,000, about 20,000, about 25,000, or about 30,000, or any range between any two of the preceding values. The PEG group can be single-chain, double-chain, branched, or cyclic or polycyclic. In certain circumstances, the higher molecular weight PEG chains can be useful in increasing the solubility of the block copolymer when conjugating multiple types of water-insoluble drugs and / or molecules.

[0051] While the description and examples focus on topical application of emulsions containing poorly water soluble active ingredient(s), it is readily apparent that the invention can serve as a platform for formulating and delivering poorly water soluble inactive ingredient(s), as well as for applying the emulsions in non-topical, e.g., intraocular, mucosal, intravenous, intramuscular, sublingual, and oral modes.

[0052] Emulsions, especially micro-, mini-, and nano-emulsions, can be advantageous for localized delivery of active (and / or inactive) ingredient(s) to different layers of the epidermis and to the systemic circulation of the body. Conventional topical treatments, e.g., gels and creams, are generally less efficient and less aesthetically appealing, which can lead to poor patient compliance or adherence, while systemic and phototherapies often result in significant adverse side effects. The small particle and droplet sizes present in nanoemulsion (approximately 5-500 nm) formulations enhance the appearance, delivery and penetration of drugs through the epidermis and layers of the skin.

[0053] The technical field of formulating topical compositions for treating diseases, illnesses or disorders via the skin involves the advanced application of multiple scientific disciplines, e.g., chemistry, biology, physics, mathematics, and materials. A common challenge for formulators is the optimal way to mix active ingredient(s) with other (active or inactive) ingredients to provide an effective, easy-to-use composition. It has been determined through experimentation that the oil-free aqueous emulsions of the invention can be used as a platform to solubilize active (as well as inactive) ingredients that are poorly water-soluble. The compositions and methods of use described herein can be useful in producing a variety of products in the multidisciplinary field.

[0054] The topical emulsion systems described herein are (substantially or completely) devoid of an oil phase and can be formulated as mini-, micro-, or nano-aqueous emulsions. (i) about 2.5% to about 50% by weight of diethylene glycol monoethyl ether (DEGEE); (ii) about 5% by weight to about 20% by weight of polyethylene glycol (PEG:H(OCH 2 CH 2 ) n OH) derivatives, where n is from 2 to about 1,000; (iii) about 60% to about 92% by weight of water; and (iv) From about 0.01% to about 2.0% by weight of a poorly water-soluble chemical compound dispersed in a substantially or completely oil-free topical emulsion.

[0055] In one embodiment, n is equal to about 30 to about 40 in the PEG chain. In certain embodiments, the PEG derivative of castor oil can be PEG40 (n=40) hydrogenated castor oil (PEG 40 HCO).

[0056] The emulsion system can be used as a formulation platform to create nanoemulsions of active ingredient(s) (e.g., flavonoids) with the substantial or complete absence of an oil phase in the emulsion. The emulsion platform can create nanoparticles (and nanodroplets) that improve the appearance of the product and efficiently deliver active (and / or inactive) ingredients locally, while addressing the inherent solubility issues of poorly water-soluble chemical compounds that adversely affect their bioavailability. The formulation platform can be used to create compositions that maintain their clarity and solubility upon further dilution with water, eliminating the need for an oil phase used in conventional mini-, nano-, and micro-oil-in-water or water-in-oil emulsions. The formulation platform offers a wide range of applications for the topical delivery of poorly water-soluble chemical compounds that cannot be effectively administered orally. The solubilized compositions can be incorporated into bases, e.g., lotions or creams, enhancing the penetration and delivery of the chemical compounds.

[0057] The formulations according to the invention provide an emulsion platform that can be useful for producing products in many industries (e.g., pharmaceuticals, cosmetics, personal care, industrial, food, etc.) In the pharmaceutical field, they can be used to produce products to treat various diseases and disorders, such as hair loss, psoriasis, cancer, inflammation, and pigmentation disorders (e.g., vitiligo and melasma).

[0058] The emulsion platform can be designed to provide preventative effects (e.g., UV protection, anti-aging protection, dietary supplements to prevent and / or treat various medical problems, etc.) or absorption of drugs that undergo high first-pass metabolism during oral or other delivery methods. It can also be used to encapsulate gene therapy products, e.g., siRNA, cccDNA, mRNA, etc.

[0059] In embodiments, inventive topical compositions containing active ingredients may further comprise inactive ingredients, such as co-solvents, co-emulsifiers, cationic, ionic or non-ionic co-surfactants, stabilizers, thickeners, antioxidants, conditioners, moisturizers, emollients, penetration enhancers, preservatives, nutrients, fragrances, pigments, colorants, dispersing agents, antipruritics, antiperspirants, antipsoriatic agents, antiseborrheic agents, anti-aging agents, anti-wrinkle agents, skin lightening agents, depigmenting agents, vitamins, nutrients, fragrances, preservatives, stabilizers, or combinations thereof.

[0060] The composition may include one or more active ingredients. For example, the active ingredient may be a natural product, such as a flavonoid (e.g., flavanol) or a polyphenol. Exemplary natural products include, but are not limited to, fisetin, trans-resveratrol, milk thistle extract with silymarin, quercetin, dihydroquercetin, curcumin (and / or turmeric), (-)-epigallocatechin-3-gallate (EGCG), rutin, diosmin, rosacea extract, imatinib, and imatinib mesylate. The active ingredient may be a hair growth promoter, or an antibiotic, antiseptic, antifungal, antibacterial, anti-inflammatory, analgesic, antiviral, anesthetic, anticancer drug (e.g., imatinib or its mesylate), or antiacne drug.

[0061] Optionally, the composition may include "natural oils" or "essential oils." Natural oils have been studied and marketed in the pharmaceutical, food, personal care, skin care and cosmetic fields for various skin disorders and other ailments. Some examples include: coconut, almond, grape seed, olive, sunflower seed, argan, rosehip seed, jojoba, marula, tea tree, and safflower oil. Similarly, essential oils have been the subject of various studies in these fields. Examples of essential oils include: lavender, chamomile, sandalwood, clary sage, rosemary, frankincense, geranium, neroli, lemon, lemongrass, cinnamon, tea tree, peppermint, wintergreen, eucalypus, patchouli, pomegranate, carrot seed, tangerine, ylang ylang, rose, myrrh, and jojoba oil.

[0062] Although both essential oils and natural oils are derived from plants, there is a difference between the two classes. Essential oils are distilled from the leaves, roots, bark, and other aromatic parts of plants or botanicals. The oils evaporate and have a concentrated aroma. Thus, essential oils are concentrated, hydrophobic liquids that contain the volatile aroma compounds derived from the plant / botanical. Due to their high potency, essential oils can cause an irritating effect on the skin and are usually diluted with a carrier oil to reduce this issue.

[0063] In contrast, natural oils are usually pressed from the fatty parts of plants or botanicals, such as seeds, nuts, or kernels. Chemically, natural oils are triglycerides, in which glycerin is esterified with three fatty acids. They are the main components of vegetable oils and animal fats. Natural oils are generally gentler on the skin than essential oils, and generally do not require the addition of a carrier oil to be used.

[0064] In embodiments, the topical composition may be in the form of an ointment, cream, emulsion, lotion, paste, salve, gel, tincture, sunscreen, spray, or other topical dosage form. The emulsions described herein may further include a cleansing agent, an emollient, or an aromatic chemical compound. The ointments, creams, lotions, and ointments according to the present invention may further include a wax, an alcohol, or a petroleum-based emollient.

[0065] Gels according to the present invention optionally contain, for example, a vegetable oil, up to about 5% by weight of the total composition. The gel may further contain water and / or a thickening agent. The thickening agent may be a natural polysaccharide, for example, xanthan gum, carrageen, alginate, and / or cellulose gum.

[0066] A paste according to the present invention may optionally contain aloe gel and / or beeswax.

[0067] Lotions according to the present invention may optionally contain cetyl alcohol, emulsifiers, fragrances, glycerol, petroleum jelly, dyes, one or more preservatives and / or stabilizers.

[0068] The sunscreen composition according to the present invention may optionally contain a UV absorbing or barrier agent, for example, in an amount of about 0.1% to 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.

[0069] The emulsion system of the invention may include antibiotics, antiseptics, antifungals, analgesics, antivirals, and / or stabilizers. Some examples of these agents are listed below.

[0070] Antibiotic agents include, but are not limited to, ampicillin, bacampicillin, carbenicillin indanyl, mezlocillin, piperacillin, ticarcillin, amoxicillin-clavulanate, ampicillin-sulbactam, benzylpenicillin, cloxacillin, dicloxacillin, methicillin, oxacillin, penicillin G, penicillin V, piperacillin-tazobactam, ticarcillin-clavulanate, nafcillin, procaine penicillin, cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephradine, cefaclor, cefamandol, cefonicid, cefotetan, cefoxitin, cefprozil, ceftmetazole, cefloxacillin, cefluroxine ... sim, 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, pefloxacin (perfloxacin), imipenem-cilastatin, meropenem, and aztreonam. In one embodiment, the amount of antibiotic in the topical composition may be from about 0.01% to about 5% by weight of the total composition.

[0071] Antiseptics include, but are not limited to, iodine, manuka honey, octenidine dihydrochloride, phenol, polyhexanide, sodium chloride, sodium hypochlorite, calcium hypochlorite, sodium bicarbonate, methylparaben, benzoyl peroxide, and sodium dehydroacetate. In one embodiment, the amount of antiseptic in the topical formulation can be from about 0.01% to about 5% by weight of the total composition.

[0072] Antifungal agents include, but are not limited to, amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole. , fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfine, butenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet, and balsam of Peru. In one embodiment, the amount of antifungal agent in the topical formulation can be from about 0.01% to about 5% by weight of the total composition.

[0073] Analgesics include, but are not limited to, methyl salicylate, codeine, morphine, methadone, pethidine, buprenorphine, hydromorphine, levorphanol, oxycodone, fentanyl, and nonsteroidal anti-inflammatory drugs. In one embodiment, the amount of analgesic in the topical formulation can be from about 0.01% to about 5% by weight of the total composition.

[0074] Antiviral agents include, but are not limited to, acyclovir, famciclovir, penciclovir, valacyclovir, trifluridine, docosanol, amantadine, rimantadine, oseltamivir, and zanamivir. In one embodiment, the amount of antiviral agent in the topical formulation can be from about 0.01% to about 5% by weight of the total composition.

[0075] Stabilizers include, but are not limited to, guar gum, xanthan gum cellulose hyaluronic acid, polyvinylpyrrolidone (PVP), alginate, chondritin sulfate, poly-gamma glutamic acid, gelatin, chitisin, corn starch, and wheat flour. In one embodiment, the amount of stabilizer in the topical formulation can be about 0.25% by weight to about 2% (w / v).

[0076] The formulation can be prepared by conventional procedures known in the fields of pharmaceuticals, cosmetics, skin care, personal care, food, and industrial chemistry.It can be recognized that the compositions described herein can be modified by well-known techniques to accommodate different amounts and types of ingredients.In addition, the specific ingredients and ratios described herein are for illustrative purposes.The ingredients can be replaced with suitable equivalents or substitutes, and the ratios can be changed according to the desired properties of the target dosage form.

[0077] 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 and 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 difficult for formulators to find the best (active and inactive) ingredients and the best loading requirements to enhance the efficacy of ingredients in a composition when it is taken orally or applied to and in contact with the skin of a human or animal. Similar limitations need to be addressed in other administration formats (intraocular, mucosal, intravenous, intramuscular, sublingual, etc.).

[0078] Those skilled in the art of topical formulations can use the compositions and methods described herein to create high quality products.The compositions according to the present invention can be applied to any part of the skin, such as the face, scalp, back and other parts of the body.Upon contact with the skin, the compositions of the invention can effectively and efficiently deliver active and / or inactive ingredients to humans or animals in need thereof and provide their beneficial attributes.

[0079] The invention includes a method for treating skin disorders and other types of ailments by applying a therapeutically effective amount of the composition of the invention to the skin of a human or animal in need of such treatment for a therapeutically effective amount of time. When the composition comes into contact with the skin, the active ingredients contained therein can treat or ameliorate various skin disorders and other types of diseases and ailments (e.g., systemic inflammation).

[0080] Skin is the largest organ that covers and protects the body. A skin disorder (i.e., disease or illness) is a condition that affects a person's skin. The disorder can result in rashes, inflammation, itching, skin damage or other harmful changes to the skin. The cause of the skin condition may be due to genetic and / or lifestyle factors. Skin disease treatment may include medications, creams, ointments, or lifestyle changes. Skin conditions include conditions that clog, irritate, or inflame the skin, causing rashes or other changes in the skin's appearance. Some skin diseases are mild, while others cause severe symptoms. Some of the more common skin diseases include: Acne - Clogged skin follicles leading to buildup of oil, bacteria and dead skin in the pores. Alopecia areata - small patches of hair loss. Atopic dermatitis (eczema) - dry, itchy skin that can lead to swelling, cracking or scaling. Psoriasis - scaly skin that may be swollen and feel hot. · Raynaud's phenomenon - periodic reduction in blood flow to the fingers, toes or other body parts causing numbness or changes in skin color. · Rosacea - Red, thick skin and breakouts, usually on the face. · Skin cancer- uncontrolled growth of abnormal skin cells. · Vitiligo - patches of skin or hair that have less pigment than the surrounding skin or hair areas. · Melasma - spots of skin (brown or gray-brown) that contain more pigment than the surrounding skin areas. · Varicose or spider veins - enlarged, twisted, damaged veins often found near the skin's surface in the legs.

[0081] Common causes of skin disorders include: · Bacteria trapped in the pores or hair follicles. ·Conditions affecting the thyroid, kidneys or immune system. · Environmental factors that cause inflammation, such as contact with allergens (e.g., poison ivy and poison sumac) or contact with the skin of another human or animal. Genetic and / or hormonal disorders. · Fungi or parasites living on the skin. Medications, such as sulfasalazine, a drug used to block inflammation in Crohn's disease, can cause allergic skin rashes, hives, or itching. Viruses, such as human papillomavirus (HPV) or herpes simplex virus (HSV). ·Diabetes mellitus and related conditions, such as diabetic dermopathy, diabetic necrobiosis lipoidica, diabetic bullosa, and eruptive xanthomatosis.

[0082] Some of the examples presented below provide an optimized oil-free topical aqueous emulsion system for the delivery of milk thistle extract with fisetin, trans-resveratrol and / or silymarin to promote hair growth. The formulations can be used to promote hair growth (e.g., to grow hair in shaved areas of the body after performing a medical procedure) to treat alopecia or for any other reason.

[0083] Other examples presented below demonstrate a broad range of topical applications of formulation techniques using: · Fisetin as a hair growth (and hair loss prevention) treatment. · Quercetin and (-)-epigallocatechin-3-gallate (EGCG) for the treatment of warts (e.g. common warts, plantar warts and flat warts) and herpes labialis. ·Curcumin for the treatment of inflammation. · Salicylic acid for treating acne. ·Pink rose (herb extract) for the treatment of hair loss, eczema, or other skin conditions involving inflammation. ·Dihydroquercetin for hair growth treatment and hair loss prevention. Rutin and trans-resveratrol for the treatment of varicose veins, and optionally, diosmin. Imatinib or imatinib mesylate for the treatment of pigmentary disorders (e.g. vitiligo and melasma).

[0084] Hair growth and hair loss prevention using the inventive formulations can occur through different modes. The inventive formulations can slow down the rate of hair loss and / or promote the growth of new hair. They can repair / reactivate inactive hair follicles and / or grow new hair follicles. They can (i) slow down, halt, and / or reverse hair follicle miniaturization; (ii) increase blood flow around the hair follicle; (iii) stimulate hair follicle migration into the growth phase; and / or (iv) prolong the growth phase of the hair follicle. The inventive formulations can promote hair growth rates of one-quarter, one-half, three-quarters, or one inch per month, or any rate in between. The growth rate can result in an increase in the concentration of hair in the treatment area of ​​about 25%, about 50%, about 75%, about 100%, or any amount in between.

[0085] Wart resolution with the formulation of the invention can occur by shedding of layers of the wart mass until it is resolved. The formulation of the invention can be applied to the wart mass until the mass is no longer visible and / or the area looks the same as the surrounding skin. Any black dots or areas of granular texture that were present are no longer visible. Wart resolution can be about 25%, about 50%, about 75%, about 100%, or any amount in between.

[0086] A commonly used synthetic emulsifier found in a variety of products is polyethylene glycol (PEG:H(OCH 2 CH 2 ) nPEG 40 HCO is a PEG derivative of castor oil, with n equal to 2 to about 1,000. For example, PEG 40 hydrogenated castor oil (a PEG derivative of castor oil abbreviated as PEG 40 HCO) functions as a multifunctional emulsifier, surfactant, foam booster, emollient, cleanser, solubilizer, thickener, and / or co-solvent. It can be found in many commercial products across various industries, such as pharmaceuticals, cosmetics, foods, skin care products, and personal care products. PEG 40 HCO does not have oil properties. However, it has exceptional emulsifying and solubilizing properties and is soluble in both water and oil. It is particularly useful in aqueous formulations containing large aqueous phases and can be combined with oils or other types of fats or lipids to prepare oil-in-water nanoemulsions with clear, stable oil droplets.

[0087] In the examples below, aqueous emulsions were formulated without the presence of an oil phase using PEG 40 HCO. Although the examples used PEG 40 HCO as the emulsifier, the emulsions of the invention can also be made using a variety of other grades of polyoxyl n hydrogenated castor oil, for example, where n is equal to about 30 to about 40 in the PEG chain.

[0088] 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, in its triglyceride form, is used as an ingredient in many foods. It is a component of the normal human diet, found in animal fats and vegetable oils. Oleic acid as its sodium salt is a major component of soap as an emulsifier. It is also used as an emollient. Small amounts of oleic acid are often used as an excipient in pharmaceuticals or as an emulsifying or solubilizing agent in aerosol products. Oleic acid is widely used in the solution-phase synthesis of nanoparticles, where it functions as a kinetic knob to control the size and morphology of the nanoparticles.

[0089] A commonly used co-solvent for solubilizing chemical compounds is diethylene glycol monoethyl ether ["DEGEE", also known as 3,6-dioxa-1-octanol, 2-(2-ethoxyethoxy)ethanol, ethoxydiglycol, or by the trade name Transcutol®]. It can be produced by the condensation of ethylene oxide and ethanol, followed by distillation. The presence of both ether and alcohol functional groups in the molecule provides excellent solubilizing capabilities. DEGEE is an odorless liquid that is primarily used as a solubilizer and permeability enhancer to produce a variety of products, such as 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 longer-lasting, more uniform coloring. There are limitations to the use of DEGEE. DEGEE cannot be used as the sole solvent (100%) and generally needs to be formulated to a concentration of less than about 50% (preferably less than about 20%) in topical formulations. (For example, there is an FDA-approved topical product that uses 49% DEGEE in the FDA Inactive Ingredients Database.) Although DEGEE does not have oil or emulsifying properties, it is a useful co-solvent due to its miscibility with water and some oils such as almond oil or oleic acid.

[0090] Oil-in-water (o / w) and water-in-oil (w / o) emulsions, which contain oil, water, surfactants (or other emulsifiers), and cosolvents, are frequently formulated to improve the appearance, delivery, and bioavailability of the active compound(s). DEGEE and PEG 40 HCO have been used to produce o / w emulsions, along with some of the compounds described herein. Most emulsions contain particles and droplets with an average diameter of > about 1 μm. However, mini-, micro-, and nano-emulsions according to the present invention can be designed with particle and droplet sizes in the range of about 100-500 nm. With the proper formulation, highly stable emulsions can be prepared with particles and droplets as small as a few nanometers.

[0091] As described above, the formulations of the invention may be useful in treating various skin disorders, such as alopecia (hair loss). Humans and animals suffer from hair loss widely. There are many types of treatments that can reverse, or at least slow, the hair loss. Treatments include medications and surgery. Two popular medications are minoxidil (Rograine®) and finasteride (Propecia®). Minoxidil is applied topically and finasteride is taken orally. Minoxidil has some side effects (e.g., scalp irritation and unwanted hair growth on the adjacent skin of the face and hands) and must be discontinued if a rash appears. Orally administered finasteride suffers from rare side effects (e.g., decreased libido and function and increased risk of prostate cancer) and is contraindicated in pregnant women due to the risk of hypospadias in the male fetus. Other oral medications include spironolactone (Carospir®, Aldactone®) and oral dutasteride (Avodart®). Other topical products that have been studied are based on natural products that contain biotin, amino acids, curcumin, and caffeine as growth supplements. Various other tinctures, serums, and mixtures of natural products have also been studied and are sometimes marketed for hair loss.

[0092] Despite the existence of various types of treatments for hair loss, their efficacy, and their side effects are undesirable. There remains a great need for more effective hair loss products. Several hair growth studies in the literature have attempted to find novel hair growth compounds that work through biological pathways different from those employed by today's commercial products (generally based on the classical androgenic alopecia model). Recent hair growth compounds include fisetin, trans-resveratrol, and silymarin (derived from milk thistle extract). These compounds are natural products that have been shown to promote growth through the JAK / STAT and Wnt / β-catenin molecular pathways. However, despite the promise of growth-promoting properties, it has been reported that compounds administered as solutions have been found to be suboptimal for long-term application (e.g., ethanol and isopentyldiol toxicity and side effects). Fisetin delivered topically using an ethanol-based formulation was reported to be unviable as it damaged hair, while trans-resveratrol delivered topically using an isopentyldiol formulation was reported to block hair follicles. Thus, these formulation vehicles are generally not commercially acceptable.

[0093] Emulsion technology has been applied to many active molecules, such as fisetin, trans-resveratrol and silymarin (derived from milk thistle extract). Fisetin, trans-resveratrol and silymarin are active components of natural products, which have been the subject of many studies addressing their hepatoprotective, antioxidant, anti-inflammatory, immunomodulatory, anticancer, cardioprotective and hair growth properties. However, studies have shown that all three compounds have low oral bioavailability, thus limiting their effectiveness. As a result, the three active compounds are not administered orally, and various formulations have been developed to deliver them locally to the body. Several studies have shown that some of the compounds can be delivered locally, mainly by using oil-in-water emulsion technology.

[0094] The structures of fisetin, trans-resveratrol, and silymarin are shown in Scheme 1 below. [ka]

[0095] Fisetin (3,3',4',7-tetrahydroxyflavone) (2-(3,4-dihydroxyphenyl)-3,7-dihydroxy-4H-1-benzopyran-4-one) (Scheme 1) is a bioactive flavonol (a flavonoid group of polyphenols) molecule found in many plants, fruits and vegetables, such as strawberries, apples, persimmons, grapes, onions, and cucumbers, at concentrations ranging from about 2-160 μg / g. Fisetin has been suggested to have antiproliferative, apoptotic, and / or antioxidant activity. Literature has reported that fisetin can be an effective chemopreventive / chemotherapeutic agent in some types of cancer and may have neuroprotective properties. However, fisetin has also been reported to have low oral bioavailability, possibly due to its poor aqueous solubility (10.45 mcg / mL) and high lipophilicity (logP 3.2). In addition, fisetin has been shown to be highly metabolized when taken orally or intravenously.

[0096] Resveratrol (5-[(E)-2-(4-hydroxyphenyl)ethen-1-yl]benzene-1,3-diol) (Scheme 1) is a natural polyphenolic stilbenoid found in various 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 bioactive compound. Classified as a phytoalexin, trans-resveratrol can be produced in response to fungal attack or the onset of certain stresses, such as trauma and UV irradiation. Trans-resveratrol has been investigated for its potential therapeutic effects in the treatment or prevention of cancer, heart disease, neurodegeneration, and inflammation. Trans-resveratrol is generally produced by isolating it from red wine / grape skin extracts or from the plant Japanese knotweed. However, it has low oral bioavailability, limiting its usefulness as a therapeutic agent in humans. The bioavailability of trans-resveratrol is approximately 0.5%, likely due to extensive hepatic glucuronidation and sulfation. The feasibility of oral delivery methods using trans-resveratrol is questionable due to its low aqueous solubility and short half-life (approximately 15 minutes).

[0097] Silymarin (Scheme 1) is a flavonolignan extracted from milk thistle Silybum marianum (L.) gaernt 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 (2R,3R)-3,5,7-trihydroxy-2-[(2R,3R)-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl]chroman-4-one. Silymarin has been shown to possess various pharmacological properties, such as hepatoprotective, antioxidant, anti-inflammatory, anticancer, antifibrotic, and cardioprotective activities. Although clinical trials have shown that silymarin is non-toxic at high doses (>approximately 1500 mg / day) in humans, pharmacokinetic studies have revealed poor absorption of the molecule, rapid metabolism, and ultimately, poor oral bioavailability.

[0098] There are many examples of oil-in-water mini-, micro-, and nano-emulsions in the literature. See, for example, U.S. Patent Nos. 10,918,606 and 10,736,842, and U.S. 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 compound class as fisetin, silymarin, and silibinin), carvedilol, nitrendipine, vinpocetine, curcumin, (-)-epigallocatechin-3-gallate (a polyphenol abbreviated as EGCG), and salicylic acid.

[0099] The molecular structures of quercetin, curcumin, (-)-epigallocatechin-3-gallate, salicylic acid, and rutin are shown in Scheme 2 below. [ka]

[0100] Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one) and dihydroquercetin are plant pigment flavonoids (flavonols) (Scheme 2). They are potent antioxidants found in many plants and foods, such as red wine, onion, asparagus, broccoli, buckwheat, green tea, grapes, apples, cherries, berries, and citrus fruits. It has been reported that quercetin has protective capabilities against tissue injury induced by various drug toxicity, exhibits antioxidant, anti-inflammatory, antibacterial, and antiviral properties, may help reduce swelling, kill cancer cells, control blood sugar, and may 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 more bioavailable than quercetin.

[0101] Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a plant-derived polyphenolic carotenoid compound (Scheme 2). It occurs naturally in the rhizomes of the yellow root plant Curcuma longa (Turmeric) and other Curcuma species. It has been the subject of intensive investigation due to its various activities (e.g., anti-inflammatory, anti-cancer, etc.) and can be found in many oral herbal supplements. Curcumin may help manage exercise-induced inflammation and muscle pain, thus enhancing recovery and performance in active people. Oral administration of curcumin generally does not lead to associated health effects due to its poor bioavailability (thought to be mainly due to poor absorption, rapid metabolism, and rapid elimination). Turmeric essential oil (ETO)-coated curcumin has been shown to have approximately 7-10 times higher bioavailability and longer retention in the systemic circulation compared to standard curcumin.

[0102] (-)-Epigallocatechin-3-gallate ([(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl]3,4,5-trihydroxybenzoate) (EGCG) is an ester of epigallocatechin and gallic acid (Scheme 2). It is a form of catechin. EGCG is a polyphenol (flavanol). It is the most abundant catechin in green tea. It has been studied for its ability to affect human health and disease due to its antibacterial, antiviral, and anticancer properties. However, when taken orally, EGCG has poor absorption even at a daily intake equivalent to about 8-16 cups of green tea. After consumption, EGCG blood levels usually peak within 1.7 hours. The absorption plasma half-life is about 5 hours, but the majority of unchanged EGCG is excreted in the urine almost immediately and by about 8 hours.

[0103] Salicylic acid (2-hydroxybenzoic acid) belongs to a class of drugs known as salicylates (Scheme 2). When applied to the skin, salicylic acid may act by reducing redness and swelling (inflammation) by helping the skin to slough off dead cells from the top layer. This application may reduce skin disorders, such as acne and warts, and accelerate skin healing by strengthening the body's immune system.

[0104] Rutin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one) (Scheme 2) (also known as rutoside, quercetin-3-rutinoside, and sophorin) is a 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., a citrus flavonoid glycoside found in buckwheat). Rutin may have antioxidant and anti-inflammatory effects. It has been investigated as a potential preventative agent against cancer and other diseases. Rutin is commonly used for autism, skin aging, exercise-induced respiratory tract infections, and other purposes, but there is little scientific evidence supporting its effectiveness.

[0105] Kshavak / Sneezewort is a leaf herb that has been used for centuries in traditional Chinese medicine to treat respiratory disorders. Twelve common components, such as flavones and their glycosides, phenols and polyphenolic acids, and sesquiterpene lactones, have been identified in the ethanol extract of Kshavak. Brevilin A is a sesquiterpene lactone isolated from Kshavak that has been shown to inhibit Janus kinase 3 (JAK3), a cellular pathway involved in hair loss and cancer treatment.

[0106] Other active ingredients, such as diosmin, imatinib, and imatinib mesylate, can be used in the aqueous emulsions described herein, and their molecular structures are shown in Scheme 3 below. [ka]

[0107] Diosmin (5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxychromen-4-one) (Scheme 3) is a disaccharide derivative, which consists of diosmetin substituted at the 7-position by a 6-O-(α-L-rhamnopyranosyl)-β-D-glucopyranosyl moiety via a glycosidic bond. It has a role as an antioxidant and anti-inflammatory agent. It is a glycosyloxyflavone, rutinoside, disaccharide derivative, monomethoxyflavone and dihydroxyflavanone. It is functionally related to diosmetin.

[0108] Imatinib (4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide) and its mesylate salt (Scheme 3) are 2-phenylaminopyrimidine derivatives that function as specific inhibitors of many tyrosine kinase enzymes. They are small molecule inhibitors that target multiple receptor tyrosine kinases, e.g., CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Imatinib mesylate is commercially available under the trade names Gleevec and Glivec, among others, and is used as an oral targeted therapy drug to treat cancer.

[0109] The above compounds were formulated using the emulsion systems of the invention and the topical compositions were applied to the skin of human subjects and tested for a variety of disorders.

[0110] The novel compositions described herein comprise chemical compounds that are poorly water-soluble in an aqueous-based emulsion that is substantially or completely free of an oil phase.Exemplary compounds include, but are not limited to, one or more of the compounds shown in Schemes 1 and 2 above.The compositions are useful for topical and other modes of application to treat various skin disorders (e.g., hair loss, plantar warts, cold sores, etc.) and other types of diseases or illnesses.

[0111] The following examples are intended to illustrate the invention and should not be construed as narrowing its scope. Those skilled in the art will readily recognize that the examples suggest other ways in which the invention can be practiced. It should be understood that many changes and modifications are possible while remaining within the scope of the invention.

[0112] Working Example Example 1. Formulation of a topical composition containing fisetin, trans-resveratrol, and milk thistle (containing silymarin) This study attempted to formulate the active ingredients fisetin, trans-resveratrol, and milk thistle extract (containing silymarin) together in a combination that would be useful as a topical composition to prevent hair loss and / or promote hair growth. This study achieved a stable, clear, oil-free aqueous nanoemulsion containing the active ingredients, polyethylene glycol (PEG) 40 hydrogenated castor oil (PEG 40 HCO), diethylene glycol monoethyl ether (DEGEE), and water, where the active ingredients were dispersed in the oil-free topical emulsion.

[0113] DEGEE is an odorless liquid co-solvent that is miscible in water and can enhance the solubility and permeability of chemical compounds when applied to human or animal skin.

[0114] PEG 40 HCO is a waxy, viscous liquid emulsifier that is miscible in water. PEG 40 HCO by itself did not effectively dissolve fisetin, trans-resveratrol, or milk thistle extract (containing silymarin) powders. It did not wet the compound powders sufficiently and was too viscous to act as a solvent by itself. However, when PEG 40 HCO was added to a DEGEE mixture containing fisetin, trans-resveratrol, and milk thistle extract (containing silymarin), dissolution of all three compounds was successfully achieved.

[0115] Fisetin, trans-resveratrol, and milk thistle extract (including silymarin) were all found to be soluble in DEGEE in a solubility screening panel evaluating surfactants and other emulsifiers for use in topical delivery. The initial objective was to find suitable miscible oils for use in hair applications, such as argan, sesame, sunflower, fractionated palm, and grape seed oil. None of the oils evaluated were miscible with DEGEE, and the resulting mixtures showed visible separation of the DEGEE and oil phases. The next step was to evaluate oil-soluble emulsifiers, such as glyceryl oleate, sorbitan oleate, lauryl oleate, and lauryl sulfate. Glyceryl oleate was found to increase the miscibility of DEGEE with argan oil. However, when the mixture was diluted with water, a suspension formed and the active ingredient precipitated out of solution. Oleic acid (a fatty acid) is known to be miscible with DEGEE, but it is a fatty acid that is less likely to clog pores, making it a poor choice for use in long-term topical formulations. Oleic acid was evaluated with a mixture of sorbitan laurate, polyglyceryl-4 laurate, and dilauryl citrate. This formulation produced a miscible mixture with fisetin, trans-resveratrol, and milk thistle dissolved in DEGEE. However, dilution of the mixture with water produced a suspension, and again, solids precipitated after approximately 1 hour.

[0116] At this point, the objectives of the study changed. Instead of further evaluating the mixture for an oil phase, it was decided to dilute the mixture directly with water and see what would happen. It was expected that further dilution with water would cause the tested active ingredient to precipitate. However, the active ingredient did not precipitate, and the diluted solution remained clear yellow in appearance and remained stable. Without being bound to a particular theory, it is hypothesized that this result indicates that a nanoemulsion had been formed, or that the PEG 40 HCO had formed a somewhat supersaturated solution. The results were surprising and unexpected, since the previous formulation contained an oil (or fatty acid) ingredient component, which produced an oil-in-water emulsion, whereas this formulation lacked an oil phase as a component of the mixture, yet still produced a stable, clear aqueous emulsion.

[0117] In light of the surprising result of producing an oil-free aqueous emulsion, the following formulation (AH) was prepared: A-Fisetin was dissolved in DEGEE at approximately 0.15% and then diluted 1:1 with water. B-trans-resveratrol was dissolved in DEGEE at approximately 0.15% and then diluted 1:1 with water. C-Silybum marianum extract (containing silymarin) was dissolved in DEGEE at approximately 0.25%, then diluted 1:1 with water. D - about 0.15% fisetin, about 0.15% trans-resveratrol, about 0.25% milk thistle extract (about 0.2% silymarin), about 10% PEG 40 hydrogenated castor oil (PEG 40 HCO), about 20% diethylene glycol monoethyl ether (DEGEE), and about 69.45% purified water. E - about 0.075% fisetin, about 0.075% trans-resveratrol, about 0.125% milk thistle extract (about 0.1% silymarin), about 5% PEG 40 hydrogenated castor oil (PEG 40 HCO), about 10% diethylene glycol monoethyl ether (DEGEE), and about 84.725% purified water (further dilution of formulation D). F - about 0.15% fisetin, about 0.15% trans-resveratrol, about 0.25% milk thistle extract (about 0.2% silymarin), about 5% PEG 40 hydrogenated castor oil (PEG 40 HCO), about 10% diethylene glycol monoethyl ether (DEGEE), and about 84.45% purified water. All mixtures (formulations AF) were stable and clear. G - about 0.15% fisetin, about 0.15% trans-resveratrol, about 0.25% milk thistle extract (about 0.2% silymarin), about 10% PEG 40 hydrogenated castor oil (PEG 40 HCO), about 10% diethylene glycol monoethyl ether (DEGEE), and about 79.45% purified water.

[0118] Formulation G remained stable and clear and was analyzed for nanoparticles (see Table I below). Nanoparticles were observed in the mixture by nanoparticle tracking technology, with a d50 particle size of about 119.5 nm and a number weighted average particle size of about 125.4 nm. This result was not expected for the mixture. A person skilled in the art of formulation development would have expected the active ingredient in the PEG 40 HCO and DEGEE mixture without the presence of an oil phase to precipitate upon dilution with water. [Table 3]

[0119] H-about 0.15% fisetin, about 0.15% trans-resveratrol, about 0.25% milk thistle extract (about 0.2% silymarin), about 5% PEG40 hydrogenated castor oil (PEG 40 HCO), about 5% diethylene glycol monoethyl ether (DEGEE), and about 89.45% purified water. Formulation H remained clear and stable, and nanoparticles were observed in the mixture by nanoparticle tracking technology, with a d50 particle size of about 37.8 nm and a number-weighted average particle size of about 36.4 nm (see Table II below). These results indicate that particle size (and droplet size) can be engineered by formulation composition. It is hypothesized that formulation H is probably a better candidate than formulation G for administration as a combination product, since smaller particle size (and droplet size) theoretically enhances the appearance and permeability of the formulation. [Table 4]

[0120] Nano-sized particles were measured using a Malvern NanoSight NS300. The NanoSight NS300 uses the technique of nanoparticle tracking analysis (NTA). This technique exploits the properties of both light scattering and Brownian motion to obtain size distribution and concentration measurements of particles in liquid suspension. A laser beam is passed through a sample chamber and particles in suspension in the path of this beam scatter light in such a way that they can be easily visualized through a 20x magnification microscope on which a camera is mounted. The camera runs at 30 frames per second (fps) and captures a video file of the particles moving under Brownian motion. The software tracks many particles individually and calculates their hydrodynamic diameter using the Stokes-Einstein equation. The measurements are controlled by standard operating procedures set up in a user-friendly software interface.

[0121] The following formulation IM was then prepared:

[0122] A base composition containing about 0.15% fisetin, about 0.15% trans-resveratrol, about 0.25% milk thistle extract (about 0.2% silymarin), and about 10% diethylene glycol monoethyl ether (DEGEE) was combined with the following amounts of PEG 40 hydrogenated castor oil (PEG 40 HCO): I-Approximately 1% PEG 40 HCO. J-approximately 2.5% PEG 40 HCO. K-approximately 5% PEG 40 HCO. L-approximately 7.5% PEG 40 HCO. M - Approximately 10% PEG 40 HCO.

[0123] Each of the formulations IM was diluted to 100% with purified water. Experiments showed that formulations I and J (containing about 1% and about 2.5% PEG 40 HCO, respectively) did not form nanoemulsions, and solid precipitation of the active ingredient was observed in both formulations. In contrast, formulations KM (containing about 5%, about 7.5%, and about 10% PEG 40 HCO) remained clear and stable.

[0124] Example 2. Formulation of a composition containing fisetin Formulations were made using fisetin as the sole active ingredient, the concentration of fisetin was increased to about 0.25% w / w fisetin, with about 2.6% DEGEE, about 8.0% PEG 40 HCO, and about 89.15% purified water in the formulation.

[0125] The formulations were prepared by dispensing the required amount of fisetin and adding it to a suitable sized container. The required amount of DEGEE was added with a magnetic stir bar and the mixture was stirred until the solids were dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the fisetin / DEGEE mixture and the three material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion.

[0126] Formulations containing about 0.25% w / w fisetin (2.5 mg / mL) represent an approximately 250-fold increase in stable nanoemulsion concentration relative to the reported aqueous solubility of about 0.01 mg / mL fisetin.

[0127] Alternate formulations were prepared using conditioner base instead of water as the diluent, and the formulation components (approximate % w / w) are summarized in Table III below. [Table 5]

[0128] The formulations produced stable and transparent nanoemulsions that can be employed via different application modes for various ailments, for example, topical compositions for the promotion of hair growth.

[0129] Example 3. Topical administration of a formulation containing fisetin to promote hair growth The formulation of Example 2 was evaluated on the scalp of a human male exhibiting thinning hair (alopecia). After 4 weeks of use of the product containing about 0.25% fisetin, about 2.6% DEGEE, about 7.5% PEG 40 HCO, and about 89.65% water, new hair growth was observed. The formulation was applied once a day after showering and towel drying the hair. The formulation was applied by dropper, gently massaged into the scalp, and allowed to air dry. Approximately 1 mL of product was applied daily. After 4 weeks of treatment, the male subject had his hair cut and hair growth was evaluated photographically. Before and after treatment photographs are shown in Figures 1a and 1b, respectively. Hair growth was observed in the vertex region of the scalp after 4 weeks of treatment. An increase in the concentration of hair present in the treated area appeared to be greater than about 25%.

[0130] Example 4. Formulation of a composition containing trans-resveratrol The formulation was made using trans-resveratrol as the sole active ingredient, and the concentrations of the ingredients in the formulation were about 0.15% w / w trans-resveratrol, about 2.6% DEGEE, about 7.5% PEG 40 HCO, and about 89.75% purified water.

[0131] The formulation was prepared by dispensing the required amount of trans-resveratrol and adding it to a suitable sized container. The required amount of DEGEE was added with a magnetic stir bar and stirred until the solid was dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the trans-resveratrol and DEGEE mixture and the three material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion.

[0132] Formulations containing about 0.15% w / w trans-resveratrol (about 1.5 mg / mL) show an approximately 50-fold increase in stable nanoemulsion concentration relative to the reported aqueous solubility of about 0.03 mg / mL trans-resveratrol.

[0133] The formulations can be employed through different modes of application for various conditions, for example, topical compositions for the promotion of hair growth.

[0134] Example 5. Preparation of a composition containing quercetin A formulation was made using quercetin as the sole active ingredient. The formulation was prepared by dispensing the required amount of quercetin and adding it to a suitable sized container. The required amount of DEGEE was added with a magnetic stir bar and the mixture was stirred until the solids were dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the quercetin and DEGEE mixture and the three material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion.

[0135] The following observations were made for each composition: Approximately 0.5% Quercetin, approximately 2.6% DEGEE, approximately 8.0% PEG 40 HCO, and approximately 88.9% water. ■ A solid precipitated after 6 hours. Approximately 0.5% Quercetin, approximately 5.0% DEGEE, approximately 8.0% PEG 40 HCO, and approximately 86.5% water. ■ Precipitation occurred after 11 hours. About 0.5% Quercetin, about 0.15% Fisetin, about 5.0% DEGEE, about 8.0% PEG 40 HCO, and about 86.35% water. ■ Precipitated after 11 hours, but 80% less solid than quercetin alone. Approximately 0.05% Quercetin, approximately 5.0% DEGEE, approximately 10.0% PEG 40 HCO, and approximately 84.95% water. ■ The nanoemulsion remained stable and transparent.

[0136] Formulations containing approximately 0.5% w / w quercetin (5 mg / mL) show an approximately 2,500-fold increase in stable nanoemulsion concentration over the reported aqueous solubility of approximately 0.002 mg / mL quercetin, even after only a few hours. Stable, clear nanoemulsion formulations containing approximately 0.05% w / w quercetin (0.5 mg / mL) show an approximately 250-fold increase over the reported aqueous solubility of quercetin.

[0137] The formulations can be employed through different modes of application for various conditions, for example, topical compositions for the promotion of hair growth.

[0138] Example 6. Formulation of a composition containing curcumin The formulations were made using curcumin as the sole active ingredient. The concentrations of the ingredients in one formulation were about 0.5% w / w curcumin, about 2.6% DEGEE, about 8.0% PEG 40 HCO, and about 88.9% purified water. Another formulation was prepared using about 0.03% w / w curcumin, about 2.6% DEGEE, about 7.5% PEG 40 HCO, and about 89.87% purified water.

[0139] The formulations were prepared by aliquoting the required amount of curcumin and adding it to a suitable sized container. The required amount of DEGEE was added with a magnetic stir bar and the mixture was stirred until the solids were dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the curcumin and DEGEE mixture and the three material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear orange nanoemulsion. After approximately 6 hours, solids precipitated from the solution containing approximately 0.5% w / w curcumin, while the formulation containing approximately 0.03% w / w curcumin was stable and clear and showed no signs of precipitation.

[0140] Formulations containing about 0.5% w / w curcumin (about 5 mg / mL) show an approximately 83,000-fold increase in stable nanoemulsion concentration over the reported aqueous solubility of 0.0006 mg / mL curcumin, albeit over only a few hours. Formulations containing about 0.03% w / w curcumin (about 0.3 mg / mL) show an approximately 500-fold increase in stable nanoemulsion concentration over the reported aqueous solubility of curcumin.

[0141] Similar formulations can be made using turmeric or a turmeric / curcumin combination as well. The formulations can be employed via different modes of application for a variety of ailments, for example, topical compositions to treat inflammation.

[0142] Example 7. Formulation of a composition containing (-)-epigallocatechin-3-gallate (EGCG) The formulation was made using EGCG as the sole active ingredient, with concentrations of the ingredients in the formulation being about 1.0% w / w EGCG, about 5.0% DEGEE, about 10.0% PEG 40 HCO, and about 84.0% purified water.

[0143] The formulations were prepared by dispensing the required amount of EGCG and adding it to a suitable sized container. The required amount of DEGEE was added with a magnetic stir bar and stirred until the solid was dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the EGCG / DEGEE mixture and the three material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion.

[0144] Formulations containing about 1.0% w / w EGCG (about 10 mg / mL) show an approximately 2-fold increase in stable nanoemulsion concentration relative to the reported aqueous solubility of about 5 mg / mL EGCG.

[0145] The formulations can be employed via different modes of application for various conditions, for example, topical compositions for the treatment of skin disorders.

[0146] Example 8. Formulation of a composition containing quercetin and EGCG The formulations were made using EGCG and quercetin as the active ingredients. The concentrations of the ingredients in one formulation were about 2.0% w / w EGCG, about 0.1% quercetin, about 5.0% DEGEE, about 10.0% PEG 40 HCO, and about 82.9% purified water. The concentrations of the ingredients in another formulation were about 1.0% w / w EGCG, about 0.05% quercetin, about 2.5% DEGEE, about 5.0% PEG 40 HCO, and about 91.45% purified water.

[0147] The formulations were prepared by aliquoting the required amounts of EGCG and Quercetin and adding them to a suitable sized container. The required amount of DEGEE was added to the EGCG / Quercetin mixture with a magnetic stir bar and the mixture was stirred until the solids were dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the EGCG / Quercetin / DEGEE mixture and the four material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion.

[0148] The formulations can be employed via different modes of application for various conditions, for example, topical compositions for the treatment of skin disorders.

[0149] Example 9. Topical administration of a formulation containing quercetin and EGCG Warts are a type of skin infection caused by a virus (Human Papillomavirus (HPV)). They can appear anywhere on the body, usually as raised, rough, flesh-colored bumps on the skin. There are five main types of warts. Each type appears on a different part of the body and has a unique appearance. Lesions on the soles of the feet are sometimes called plantar warts. This is defined as a wart that grows inwards and can occur as a result of everyday pressure on the feet. It can cause severe pain and discomfort.

[0150] Salicylic acid, up to about 40% concentration, is an over-the-counter treatment for warts. Salicylic acid peels off layers of skin, removing the wart over time. The acid also irritates (burns) the wart area, which encourages the immune system to respond to the virus. However, it works slowly and requires frequent applications for up to about 12 weeks to effectively treat skin containing the HPV virus. Cryotherapy with liquid nitrogen to freeze the wart is another preferred option for many patients, with a cure rate of about 50 percent to about 70 percent after three or four treatments.

[0151] A formulation containing EGCG and quercetin was evaluated as an antiviral treatment for the presence of several plantar warts on the soles of the right and left feet of a human male. The warts were treated with a product containing about 0.1% quercetin, about 2.0% EGCG, about 5% DEGEE, and about 10% PEG 40 HCO in an aqueous system. The formulation was applied to the affected area (where the warts were located) twice daily, once in the morning after showering and again just before bedtime. The formulation was applied to the affected area with a cotton swab and allowed to air dry.

[0152] Wart resolution was evaluated by photographs taken approximately 4 weeks after treatment. The warts on the male's feet were painful when standing or walking. Within 2 days of applying the product, the pain was substantially relieved. After approximately 2 weeks of applying the product, the viral roots of the warts on the left foot fell off. After approximately 4 weeks of applying the product, the viral roots of the two warts on the right foot fell off. Photographs at approximately 4 weeks showing the absence of viral wart masses before and after treatment on both feet can be seen in Figures 2a and 2b (left foot), respectively, and Figures 3a and 3b (right foot), respectively. Pictorial illustrations showing the removal of the wart mass from the treated wart mass on the human male's foot, and the virus and roots of the wart, are shown in Figures 4a and 4b, respectively. The results of the EGCG / quercetin formulation are surprising, suggesting that the formulation acts as an antiviral therapeutic agent against warts. It also suggests that the formulation will be similarly effective in treating herpes labialis.

[0153] Example 10. Formulation of a composition containing salicylic acid The formulation was prepared using salicylic acid as the sole active ingredient, and the concentrations of the ingredients in the formulation were about 0.5% w / w salicylic acid, about 5.0% DEGEE, about 10.0% PEG 40 HCO, and about 84.5% purified water.

[0154] The formulations were prepared by dispensing the required amount of salicylic acid and adding it to a suitable sized container. The required amount of DEGEE was added with a magnetic stir bar and the mixture was stirred until the solids were dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the salicylic acid / DEGEE mixture and the three material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion.

[0155] Formulations containing about 0.5% w / w salicylic acid (about 5 mg / mL) show an approximately 2-fold increase in stable nanoemulsion concentration relative to the reported aqueous solubility of about 2.48 mg / mL salicylic acid.

[0156] The formulations can be employed via different modes of application for various conditions, for example, topical compositions for the treatment of skin disorders.

[0157] Example 11. Formulation of composition containing milk thistle (containing silymarin) A formulation was made using Milk Thistle (containing silymarin) as the sole active ingredient. The concentrations of the ingredients in the formulation were about 0.25% w / w Milk Thistle (containing about 0.20% silymarin), about 2.6% DEGEE, about 7.5% PEG 40 HCO, and about 89.65% purified water.

[0158] The formulations were prepared by aliquoting the required amount of Milk Thistle and adding it to a suitable sized container. The required amount of DEGEE was added along with a magnetic stir bar and the mixture was stirred until the solids were dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the Milk Thistle / DEGEE mixture and the three material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a stable, clear nanoemulsion.

[0159] Formulations containing approximately 0.2% w / w silymarin (2 mg / mL) show an approximately 5-fold increase in stable nanoemulsion concentration relative to the reported aqueous solubility of approximately 0.4 mg / mL silymarin.

[0160] The formulations can be employed through different application modes for various ailments, for example, topical compositions for promoting hair growth, vitiligo, and melasma.

[0161] Example 12. Formulation of a composition containing an extract of Passiflora japonica A formulation was made using Passiflora extract as the sole active ingredient, which demonstrated extraction of herbal active ingredients with DEGEE. Dried Passiflora was ground in a coffee grinder with blades to produce a fine powder and added to a suitable sized container. The required amount of DEGEE was added to the ground powder with a magnetic stir bar at approximately a 4:1 extraction ratio, and the mixture was stirred until the solids were dissolved. The resulting liquid mixture was allowed to stir on a magnetic stir plate for approximately 6 hours. The liquid was collected in a syringe and then filtered through a 1.4 μm glass syringe filter. A dark green, stable, clear Passiflora extract / DEGEE mixture was collected.

[0162] PEG 40 HCO is semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the Passiflora extract / DEGEE mixture, and the three components were mixed on a magnetic stir plate until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion. The concentrations of the components in the nanoemulsion formulation were approximately 3.0% DEGEE extract mixture, approximately 7.5% PEG 40 HCO, and approximately 89.5% purified water. The Passiflora extract / DEGEE / PEG 40 HCO nanoemulsion was stable and clear.

[0163] The Passiflora extract / DEGEE mixture and the Passiflora extract / DEGEE / PEG 40 HCO nanoemulsion were each diluted with water in an approximately 1:1 ratio. However, components that were soluble in DEGEE precipitated out of solution when water was added to the Passiflora extract / DEGEE mixture, forming a cloudy suspension. However, components in the Passiflora extract / DEGEE / PEG 40 HCO nanoemulsion remained stable and transparent.

[0164] Nanoemulsion formulations can be employed for various ailments through different application modes, for example, topical compositions for promoting hair growth.

[0165] Example 13. Preparation of a composition containing dihydroquercetin A formulation was prepared using dihydroquercetin as the active ingredient, with the concentrations of ingredients in the formulation being about 0.1% w / w dihydroquercetin, about 2.6% DEGEE, about 7.5% PEG 40 HCO, about 88.8% purified water, and about 1.0% preservatives.

[0166] The formulations were prepared by dispensing the required amount of dihydroquercetin and adding it to a suitable sized container. The required amount of DEGEE was added with a magnetic stir bar and the mixture was stirred until the solids were dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the dihydroquercetin / DEGEE mixture and the three material components were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion to which the preservatives were subsequently added.

[0167] The formulations can be employed via different modes of application for a variety of conditions, for example, topical compositions for promoting hair growth or for treating skin disorders.

[0168] Example 14. Formulation of a composition containing rutin and trans-resveratrol A formulation was made using rutin and trans-resveratrol as the active ingredients, with concentrations of the ingredients in the formulation being about 0.05% w / w rutin, about 0.15% trans-resveratrol, about 2.6% DEGEE, about 5.0% PEG 40HCO, about 1.0% preservative, about 1.0% xanthan gum, and about 90.2% purified water.

[0169] The formulations were prepared by dispensing the required amount of rutin and resveratrol into a suitable sized container. The required amount of DEGEE was added to the container with a magnetic stir bar and the mixture was stirred until the solids were dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to >50°C and added to the rutin / trans-resveratrol / DEGEE mixture and the ingredients were mixed until uniform. The required amount of purified water was added to the mixture with stirring to produce a clear nanoemulsion, followed by the addition of preservatives and xanthan gum.

[0170] The formulations can be employed via different modes of application for various conditions, for example, topical compositions for the treatment of varicose veins.

[0171] Example 15. Formulation of a topical composition containing Imatinib (Prophetic) The formulation can be prepared using imatinib free base as the active ingredient, and the concentrations of the ingredients in the formulation will be about 0.5% w / w imatinib, about 2.6% DEGEE, about 7.5% PEG 40 HCO, about 88.4% purified water, and about 1.0% preservatives.

[0172] The formulation is prepared by dispensing the required amount of imatinib and adding it to a suitable sized container. The required amount of DEGEE is added to the container with a magnetic stir bar and the mixture is stirred until the solids are dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It is heated to >50°C and added to the imatinib / DEGEE mixture and the three material components are mixed until uniform. The required amount of purified water is added to the mixture with stirring to produce a clear nanoemulsion, followed by the addition of a preservative. The resulting formulation can be used topically to treat vitiligo and melasma.

[0173] Example 16. Formulation of a topical composition containing imatinib mesylate (prophetic) The formulation can be manufactured using imatinib mesylate as the active ingredient, and the concentrations of the ingredients in the formulation will be about 0.5% w / w imatinib mesylate, about 2.6% DEGEE, about 7.5% PEG 40 HCO, about 88.4% purified water, and about 1.0% preservatives.

[0174] The formulation is prepared by dispensing the required amount of imatinib mesylate and adding it to a suitable sized container. The required amount of DEGEE is added to the container with a magnetic stir bar and the mixture is stirred until the solids are dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It is heated to >50°C and added to the imatinib mesylate / DEGEE mixture and the three material components are mixed until uniform. The required amount of purified water is added to the mixture with stirring to produce a clear nanoemulsion, followed by the addition of a preservative. The resulting formulation can be used topically to treat vitiligo and melasma.

[0175] Example 17. Formulation of a topical composition containing rutin, trans-resveratrol, and diosmin (Prophetic) A formulation can be made using rutin, trans-resveratrol, and diosmin as the active ingredients, with the concentrations of the ingredients in the formulation being about 0.05% w / w rutin, about 0.15% resveratrol, about 2.6% DEGEE, about 7.5% PEG 40 HCO, 1.0% preservative, about 1.0% xanthan gum, and about 87.75% purified water.

[0176] The formulation is prepared by dispensing the required amount of rutin, trans-resveratrol, and diosmin and adding the three material components to a suitable size container. The required amount of DEGEE is added to the container with a magnetic stir bar and the mixture is stirred until the solids are dissolved. PEG 40 HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It is heated to >50°C and added to the rutin / trans-resveratrol / diosmin / DEGEE mixture and the material components are mixed until uniform. The required amount of purified water is added to the mixture with stirring to produce a clear nanoemulsion, followed by the addition of preservatives and xanthan gum. The resulting formulation can be used topically to treat varicose veins.

[0177] Although specific embodiments have been described above with reference to disclosed embodiments and examples, such embodiments are merely illustrative and do not limit the scope of the present invention. Changes and modifications are possible according to ordinary skill in the art without departing from the invention in its broader aspects as defined in the following claims.

[0178] All publications, patents, and patent documents are incorporated herein by reference as if individually incorporated by reference. No limitations inconsistent with the present disclosure should be understood therefrom. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that variations and modifications can be made while remaining within the spirit and scope of the invention.

Claims

1. A substantially or completely oil-free, optically transparent, transdermal aqueous emulsion, (i) Approximately 2.5% to 50% by weight of diethylene glycol monoethyl ether (DEGEE); (ii) Approximately 5% to 20% by weight of a polyethylene glycol (PEG) derivative of castor oil (where the PEG component of the derivative has the chemical formula (-OCH₂CH₂)nOH, and n is 2 to approximately 1,000); (iii) Approximately 60% to 92% by weight of water; and (iv) A compound with low water solubility dispersed in the emulsion in an amount of approximately 0.01% to approximately 2% by weight; Includes, The aqueous emulsion substantially or completely lacks an oil phase. Water-based emulsion.

2. The aqueous emulsion according to claim 1, wherein the compound with low water solubility includes a natural product.

3. The aqueous emulsion according to claim 1, wherein the low water solubility compound comprises fisetin, trans-resveratrol, milk thistle extract containing silymarin, quercetin, dihydroquercetin, curcumin, turmeric, (-)-epigallocatechin-3-gallate (EGCG), rutin, salicylic acid, diosmin, imatinib, imatinib mesylate, and / or tokinsou extract.

4. The aforementioned low water solubility compound is (i) Milk thistle extract containing fisetin, trans-resveratrol, and / or silymarin; (ii) EGCG and / or quercetin or dihydroquercetin; (iii) salicylic acid; or (iii) Rutin, trans-resveratrol, and / or diosmin; The aqueous emulsion according to claim 3, comprising:

5. The aqueous emulsion according to claim 1, wherein the PEG derivative of castor oil comprises PEG 40 hydrogenated castor oil (PEG 40 HCO).

6. (i) about 2.5% by weight to about 20% by weight of DEGEE; and (ii) Approximately 5% to 10% by weight of the castor oil PEG derivative; The aqueous emulsion according to claim 1, comprising:

7. The aqueous emulsion according to claim 1 comprises, in the following proportions, a milk thistle extract containing fisetin, trans-resveratrol, and / or silymarin, as the low water-soluble compound: (i) Fisetin in an amount of approximately 0.075% to 0.25% by weight; (ii) Approximately 0.075% to approximately 0.15% by weight of trans-resveratrol; and / or (iii) A milk thistle extract comprising approximately 0.125% to approximately 0.25% by weight, wherein the milk thistle extract contains approximately 0.1% to approximately 0.2% by weight of silymarin.

8. The aqueous emulsion according to claim 1, wherein the low water solubility compound comprises about 0.05% to about 0.1% quercetin or dihydroquercetin.

9. The aforementioned low water solubility compound is (i) about 0.03% to about 0.1% curcumin or turmeric; and / or (ii) Approximately 1% to 2% (-)-epigallocatechin-3-gallate (EGCG); The aqueous emulsion according to claim 1, comprising:

10. The aforementioned low water solubility compound is (i) about 1% to about 2% of (-)-epigallocatechin-3-gallate (EGCG); and (ii) Approximately 0.05% to 0.1% quercetin or dihydroquercetin; The aqueous emulsion according to claim 4, comprising:

11. The aqueous emulsion according to claim 1, wherein the compound with low water solubility contains about 0.1% to about 1% salicylic acid.

12. The aforementioned low water solubility compound is (i) about 0.25% to about 0.75% rutin; and / or (ii) Approximately 0.075% to 0.15% by weight of trans-resveratrol; The aqueous emulsion according to claim 1, comprising:

13. The aqueous emulsion according to claim 1, formulated as a nanoemulsion containing nanoparticles having a d50 particle size and a number-weighted average particle size, respectively, of less than approximately 150 nm.

14. The aqueous emulsion according to claim 1, which is formulated for local, intraocular, mucosal, intravenous, intramuscular, or oral administration to a human or animal requiring the aqueous emulsion.

15. The aqueous emulsion according to claim 14, formulated for topical administration.

16. A method for promoting hair growth or treating a skin disorder or varicose veins in a person or animal in need, comprising topically applying a therapeutically effective amount of a substantially or completely oil-free, optically clear, transdermal-penetrating aqueous emulsion to the skin of the person or animal for a therapeutically effective duration. The aqueous emulsion is (i) Approximately 2.5% to 50% by weight of diethylene glycol monoethyl ether (DEGEE); (ii) Approximately 5% to 20% by weight of a polyethylene glycol (PEG) derivative of castor oil (where the PEG component of the derivative has the chemical formula (-OCH₂CH₂)nOH, and n is 2 to approximately 1,000); (iii) Approximately 60% to 92% by weight of water; and (iv) A compound with low water solubility dispersed in the emulsion in an amount of approximately 0.01% to approximately 2% by weight; Includes, The aqueous emulsion substantially or completely lacks an oil phase. method.

17. The method according to claim 16, wherein the low water solubility compound comprises fisetin, trans-resveratrol, milk thistle extract containing silymarin, quercetin, dihydroquercetin, curcumin, turmeric, (-)-epigallocatechin-3-gallate (EGCG), rutin, salicylic acid, diosmin, imatinib, imatinib mesylate, and / or tokinsou extract.

18. The aforementioned low water solubility compound is (i) Milk thistle extract containing fisetin, trans-resveratrol, and / or silymarin; (ii) EGCG and / or quercetin or dihydroquercetin; (iii) salicylic acid; or (iii) Rutin, trans-resveratrol and / or diosmin; The emulsion according to claim 17, comprising:

19. A method for producing the aqueous emulsion described in Claim 1, (i) Dissolve a compound with low water solubility in an amount of approximately 0.05% to approximately 2% by weight in approximately 2.5% to approximately 50% by weight of diethylene glycol monoethyl ether (DEGEE); (ii) Diluting the mixture from step (i) with water in an amount of about 60% to about 92% by weight; and (iii) Adding approximately 5% to approximately 20% by weight of a polyethylene glycol (PEG) derivative of castor oil (where the PEG component of the derivative has the chemical formula (-OCH₂CH₂)nOH, and n is 2 to approximately 1,000) to the mixture of step (ii); Includes, The aqueous emulsion substantially or completely lacks an oil phase. method.

20. The method according to claim 19, wherein the low water-soluble compound comprises fisetin, trans-resveratrol, milk thistle extract containing silymarin, quercetin, dihydroquercetin, curcumin, turmeric, (-)-epigallocatechin-3-gallate (EGCG), rutin, salicylic acid, diosmin, imatinib, imatinib mesylate, and / or tokinsou extract.

21. The aqueous emulsion according to claim 1, comprising about 7.5% to about 20% by weight of the castor oil PEG derivative.

22. A substantially or completely oil-free, optically transparent, transdermal aqueous emulsion, which is essentially, (i) Approximately 2.5% to 50% by weight of diethylene glycol monoethyl ether (DEGEE); (ii) Approximately 5% to 20% by weight of a polyethylene glycol (PEG) derivative of castor oil (where the PEG component of the derivative has the chemical formula (-OCH₂CH₂)nOH, and n is 2 to approximately 1,000); (iii) Approximately 60% to 92% by weight of water; and (iv) A compound with low water solubility dispersed in the emulsion in an amount of approximately 0.01% to approximately 2% by weight; It consists of, The aqueous emulsion substantially or completely lacks an oil phase. Water-based emulsion.

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