Emulsion formulations of poorly water-soluble compounds

Abstract

An aqueous emulsion system substantially free of an oil phase or completely free of an oil phase. The aqueous emulsion can be used as a platform for dissolving poorly water-soluble compounds for use in a variety of fields, including pharmaceutical, cosmetic, skin care, personal care, food and industrial fields. The aqueous emulsions can be delivered to humans or animals in various ways to treat various diseases, such as topical compositions that promote hair growth or treat skin disorders. The stable and clear formulations of the aqueous nanoemulsions described herein are useful for the treatment and / or prevention of alopecia, the treatment of warts and herpes labialis, or the treatment of varicosity.

Description

[0001] Related Applications

[0002] This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Patent Application No. 63 / 331,628, filed on April 15, 2022, which is incorporated herein by reference. Background Art

[0003] Emulsions are used in a variety of industrial, cosmetic, personal care, skin care and pharmaceutical products, including ocular, topical, mucosal, intravenous, intramuscular, sublingual and oral products. Emulsions are also used as precursors for the preparation of polymer 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. Even though they are widely used, they remain an underutilized form of pharmaceutical products.

[0004] It is challenging to combine poorly water-soluble compounds in water-based 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 form an emulsion colloid by mixing an oil phase and an aqueous phase with an emulsifier. This type of emulsion colloid has an oil phase, an aqueous phase and a surfactant or other emulsifier, and may also contain a co-solvent to help dissolve the poorly water-soluble compound.

[0005] 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 compounds with poor water solubility (but soluble in oil) can be dispersed. Emulsions are thermodynamically stable, isotropic systems in which two immiscible liquids (e.g., oil and water) are mixed with an emulsifier (e.g., surfactant + co-surfactant) to form a single dispersion. One of the immiscible liquids is dispersed in the other immiscible liquid (external phase) in the form of very small globules (internal phase). The resulting emulsion is a kinetically stable and clear (i.e., transparent or translucent) dispersion of the two immiscible phases. Although the liquids that form the emulsion may be transparent, the emulsion may appear cloudy or colored due to the scattering of light by the suspended particles in the mixture.

[0006] Poorly water-soluble compounds can have an adverse effect on the appearance and efficacy of the compound in the product. Poorly water-soluble active compounds have reduced bioavailability in products (such as pharmaceutical products, cosmetics or foods), especially in products with high water concentrations. Some active compounds cannot be administered orally because oral administration is ineffective or can cause harm (for example, rapid metabolism, toxicity problems, side effects, etc. caused by short half-life). Oil-in-water and water-in-oil emulsions including oil, water, surfactants (or other emulsifiers) and cosolvents have been formulated and studied with poorly water-soluble active ingredients. These studies show that an oil phase is usually required in the composition to form a water-based emulsion system containing one or more different types of poorly water-soluble active and inactive compounds.

[0007] Although various formulations have been developed, their effectiveness and side effects are less than ideal. Better formulations are needed to effectively deliver poorly water-soluble active and inactive compounds to humans or animals. There remains a need for improved formulations containing poorly water-soluble active and inactive compounds. There is a need for new water-based topical compositions containing poorly water-soluble active and inactive compounds.

[0008] The method described in this patent attempts to meet these needs by providing a novel water-based emulsion system that does not require the presence of a large or complete oil phase. The emulsion system described herein can be used to formulate a platform for oil-free aqueous compositions containing poorly water-soluble active and inactive compounds, which is beneficial for the treatment of various skin disorders and other types of diseases and ailments. Summary of the invention

[0009] The present invention describes an aqueous emulsion system that is substantially free of an oil phase or completely free of an oil phase, the aqueous emulsion system comprising a combination of the following materials:

[0010] (i) from about 2.5% to about 50% by weight of diethylene glycol monoethyl ether (DEGEE);

[0011] (ii) about 5% to about 20% by weight of polyethylene glycol (PEG:H(OCH2CH2)) of castor oil n OH) derivatives, wherein n is 2 to about 1000;

[0012] (iii) from about 60% to about 92% by weight water; and

[0013] (iv) from about 0.05% to about 2.0% by weight of a poorly water-soluble compound dispersed in a substantially or completely oil-free emulsion.

[0014] Emulsion systems can serve as a platform for the delivery of poorly water soluble compounds by a variety of routes, such as orally, sublingually, topically or by infusion. Emulsion systems are particularly suitable for topical cutaneous (skin) therapeutic applications.

[0015] In some embodiments, in the PEG chain of the polyethylene glycol derivative of castor oil, n is equal to about 30 to about 40. In certain embodiments, the polyethylene glycol derivative of castor oil is PEG 40 hydrogenated castor oil (PEG 40HCO).

[0016] The oil-free aqueous composition can be a mini-emulsion, a micro-emulsion or a nano-emulsion. The d50 nano-particle size and the number weighted average nano-particle size of the nano-emulsion can be both less than about 150 nm. The content of the ingredients in the optimized composition can reduce or increase the particle size and droplet size. The d50 nano-particle size and the number weighted average nano-particle size of an exemplary embodiment are both less than about 50 nm.

[0017] Oil-free aqueous emulsions can be advantageously used to dissolve active ingredients and inactive ingredients that are poorly water-soluble. In embodiments, the active ingredient can be a natural product, such as a flavonoid (e.g., flavanol) or a polyphenol. Illustrated below are oil-free aqueous emulsions containing one or more of the following different natural products - fisetin, trans-resveratrol, milk thistle extracts containing silymarin, quercetin (or dihydroquercetin), (-)-epigallocatechin gallate (EGCG), salicylic acid, turmeric, curcumin (or turmeric), rutin, diosmin and imatinib or imatinib mesylate. These natural products have become the subject of many potential use studies, including the treatment and prevention of hair loss.

[0018] In one embodiment, a hair growth composition is prepared, the composition comprising:

[0019] (i) from about 2.5 wt % to about 20 wt % DEGEE;

[0020] (ii) from about 5 wt % to about 10 wt % PEG 40HCO;

[0021] (iii) from about 60% to about 92% by weight water; and

[0022] (iv) an active compound having poor water solubility, the active compound comprising:

[0023] (a) from about 0.075% to about 0.250% by weight of fisetin;

[0024] (b) from about 0.075% to about 0.150% by weight of trans-resveratrol; and / or

[0025] (c) from about 0.125% to about 0.250% by weight of a milk thistle extract containing from about 0.1% to about 0.2% by weight of silymarin.

[0026] The present invention also includes methods of application that can be beneficial for treating various skin disorders. These examples illustrate various topical applications. Two exemplary skin disorders that can be effectively treated with the preparations described herein are alopecia and human papillomavirus (HPV) warts, which are carried out by topically applying a preparation containing a desired active ingredient in a therapeutically effective amount to the affected area of ​​the skin disorder of a person or animal in need thereof within a therapeutically effective amount of time. The emulsion system can be used as a platform for manufacturing preparations with various poorly water-soluble compounds (including natural and synthetic compounds, active and inactive compounds). Emulsions can be used for applications other than topical (e.g., ocular, mucosal, intravenous, intramuscular and oral products). Depending on the active ingredient selected, emulsions can be used to treat a variety of ailments (e.g., psoriasis, cancer, inflammation and pigmentary diseases (such as vitiligo and chloasma)) other than the diseases listed herein.

[0027] The present invention also includes a method of formulating the oil-free aqueous emulsion.

[0028] The above and other objects and features of the present disclosure will become more apparent through the following detailed description with reference to the accompanying drawings. Other embodiments, forms, features, aspects, benefits, objects and advantages of the present invention will become apparent through the detailed description and drawings provided herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] The following drawings form part of the specification and are included to further illustrate certain embodiments or aspects of the present invention. In some cases, embodiments of the present invention may be best understood by reference to the drawings in conjunction with the detailed description given herein. The description and drawings may highlight a specific example or aspect of the present invention. However, those skilled in the art will appreciate that portions of the example or aspect may be used in conjunction with other examples or aspects of the present invention. These features, objects and advantages will become more apparent when considering the detailed description below. The detailed description makes reference to the following drawings:

[0030] Figure 1 : Photographs of a male scalp (after haircut) before (a) and four weeks after (b) treatment with a nanoemulsion formulation containing fisetin.

[0031] Figure 2 : Photographs of the left foot of a man with warts before (a) and four weeks after (b) treatment with a nanoemulsion formulation containing (-)-epigallocatechin gallate (EGCG) and quercetin;

[0032] Figure 3 : Photographs of the right foot of a male with two warts before (a) and four weeks after (b) treatment with a nanoemulsion formulation containing (-)-epigallocatechin gallate (EGCG) and quercetin; and

[0033] Figure 4 : A photograph showing the removal of a wart-like lump on a male's foot (a) and an illustration of the virus and roots in the wart-like lump (b).

[0034] Although the present invention may have various modifications and alternative forms, exemplary embodiments are shown by way of example in the accompanying drawings and are described in detail herein. However, it should be understood that the description of the exemplary embodiments is not intended to limit the present invention to the specific forms disclosed. On the contrary, it is intended to cover all modifications, equivalents and substitutes that fall within the spirit and scope of the present invention defined by the embodiments herein and the claims below. Therefore, the scope of the present invention should be interpreted with reference to the embodiments and claims. DETAILED DESCRIPTION

[0035] The novel oil-free aqueous emulsion system described herein can be used as a platform for solubilizing poorly water-soluble active and inactive ingredients. The following are definitions of some terms used in this disclosure.

[0036] definition.

[0037] The following definitions are included for a clear and consistent understanding of the specification and claims. As used herein, the referenced terms have the following meanings. All other terms and phrases used in this specification have ordinary meanings that are understood by those skilled in the art. Such ordinary meanings can be obtained by reference to technical dictionaries, such as Hawley's Condensed Chemical Dictionary, 14th edition, published by RJ Lewis, John Wiley & Sons, New York, New York, 2001.

[0038] References in the specification to "one embodiment", "an embodiment", etc., indicate that the described embodiment may include a particular aspect, feature, structure, part or characteristic, but not every embodiment must include the aspect, feature, structure, part or characteristic. In addition, these phrases may, but do not necessarily, refer to the same embodiment mentioned in other parts of the specification. In addition, when specific aspects, features, structures, parts or characteristics are described in conjunction with an embodiment, whether or not explicitly described, those skilled in the art will understand that these aspects, features or characteristics will affect or be associated with other embodiments.

[0039] Unless the context clearly dictates otherwise, the singular forms "a," "an," and "the" include plural referents. Thus, for example, reference to "a compound" includes a plurality of such compounds, and thus compound X includes a plurality of compounds X. It should also be noted that the claims may be drafted to exclude any optional elements. Therefore, this statement is intended to serve as a reference basis for use of exclusive terminology, such as "only," "only," and the like, in connection with any element described herein, and / or for reciting claim elements or using a "negative" limitation.

[0040] The term "and / or" refers to any one item, any combination of items, or all items associated with the term. The phrase "one or more" is easily understood by those skilled in the art, especially when reading the context in which it is used. For example, the phrase can mean one, two, three, four, five, six, ten, 100, or any upper limit that is about 10 times, 100 times, or 1000 times higher than the quoted lower limit.

[0041] As will be appreciated by those skilled in the art, all numbers, including those representing amounts, properties, purity, reaction conditions, etc., are approximate values ​​and are understood to be modified in all cases by the term "about". These values ​​may vary depending on the desired goals to be achieved by those skilled in the art using the teachings described herein. It should also be understood that these values ​​inherently contain variability that necessarily results from the standard deviations found in the respective test measurements. When a value is expressed as an approximation by using the preceding word "about", it should be understood that the value without the modifier "about" also forms another aspect.

[0042] The terms "about" and "approximately" are used interchangeably. Both terms can refer to a variation of ±5%, ±10%, ±20%, or ±25% of a specified value. For example, in some embodiments, "about 50%" can have a variation from 45% to 55%, or as defined by a particular claim. For integer ranges, the term "about" can include one or two integers greater than and / or less than the listed integers at both ends of the range. Unless otherwise specified herein, the terms "about" and "approximately" are intended to include values ​​close to the listed ranges, such as weight percentages, which are equivalent in terms of the functionality of the individual components, compositions, or embodiments. The terms "about" and "approximately" can also modify the endpoints of the listed ranges discussed above in this paragraph.

[0043] As will be understood by those skilled in the art, all numbers, including those expressing amounts, properties, reaction conditions, etc., are approximate and are understood to be modified in all instances by the term "about". These values ​​may vary depending upon the desired properties to be achieved by those skilled in the art utilizing the teachings described herein. It is also understood that these values ​​inherently contain the variability that necessarily results from the standard deviation found in their respective testing measurements.

[0044] As will be understood by those skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges listed herein also include any and all possible subranges and combinations of subranges thereof, as well as individual values, particularly integer values, constituting the range. The ranges listed (e.g., weight percentages) include each specific value, integer, decimal or unit element within the range. Any listed range can be easily considered to be fully described and capable of decomposing the same range into at least equal halves, thirds, quarters, fifths or tenths. As a non-limiting example, each range discussed herein can be easily decomposed into the lower third, the middle third and the upper third, etc. As will be understood by those skilled in the art, all languages, such as "at most", "at least", "greater than", "less than", "exceeding", "or more", etc., include the numbers listed, and these terms refer to ranges that can be subsequently subdivided into subranges as described above. In the same manner, all ratios listed herein also include all subratios that fall within the wider ratios. Therefore, the specific values ​​listed for groups, substituents and ranges are for illustration only; they do not exclude other limiting values ​​of groups and substituents or other values ​​within the limiting ranges.

[0045] Those skilled in the art will also readily recognize that where members are grouped together in a common manner, such as in Markush groups, the present invention includes not only the entire group listed as a whole, but also each individual member of the group and all possible subgroups of the main group. Furthermore, for all purposes, the present invention includes not only the main group, but also the main group lacking one or more group members. Thus, the present invention contemplates the explicit exclusion of any one or more members of the listed groups. Thus, a restrictive clause may apply to any disclosed class or embodiment, whereby any one or more of the listed elements, species, or embodiments may be excluded from these classes or embodiments, for example, for explicit negative limitations.

[0046] The terms "contacting" or "administering" means contacting, bringing into contact, or bringing into direct or close contact, including, for example, at a cellular or molecular level, to induce a physiological response, a chemical reaction, or a physical change, 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.

[0047] An "effective amount" refers to an amount effective to produce the recited effect, such as the amount of an ingredient or combination of ingredients required to form a product in a reaction mixture, the amount of a composition required to produce a therapeutic effect, or the amount of time required to apply a composition to produce a therapeutic effect. The determination of an effective amount is generally within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. Thus, an "effective amount" generally refers to an amount that provides a desired effect.

[0048] The term "substantially" as used herein is a broad term used in its usual sense, including, but not limited to, to a large extent but not necessarily completely as specified. For example, the term may refer to a value that may not be 100% of the total value. The total 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%.

[0049] A "topical" drug product is one that is applied to the cutaneous (skin) or other external tissue surface (e.g., mucous membranes) to treat a condition of the skin or other tissue to which the drug product is applied. Common forms of topical preparations include ointments, lotions, creams, solutions, gels, and foams.

[0050] A "dispersion" in chemistry is a mixture in which fine particles of one substance are dispersed throughout another. The two phases can be in the same or different states of matter (e.g., gas, fluid, liquid, or solid). Dispersions can be classified as suspensions, colloids, or solutions. Typically, the particles in a solution are molecular or ionic in size; the particles in a colloid are larger but too small to be seen with an ordinary microscope; and the particles in a suspension can be seen under a microscope or with the naked eye. Coarse mixtures (e.g., a mixture of sand and sugar) are generally not considered dispersions.

[0051] The dispersion of fine particles in liquids plays an important role in many processes in particle technology. Particles suspended in a liquid phase are called solid / liquid dispersions. There are two general methods for preparing solid / liquid dispersions: (1) reducing the size of the solid phase in the liquid to ensure homogeneity, and (2) precipitating fine particles in the liquid phase. Surfactants can be used to enhance the wettability of solids in the liquid phase. Viscosity modifiers can be incorporated into the liquid phase to reduce the sedimentation of particles dispersed in the liquid phase.

[0052] As used herein, "precipitation" refers to the settling of solid material (precipitate) from a liquid solution, wherein the amount of the material is greater than its solubility in the liquid.

[0053] An "emulsion" can be defined as a colloid consisting of two or more heterogeneous types of liquids, one of which contains a dispersion of the other. An emulsion consists essentially of a dispersion of two mutually immiscible liquids. One liquid acts as the dispersion medium and the other 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 droplets dispersed in water. The term emulsion can also be applied to a group of mixed systems such as solutions, gels or suspensions.

[0054] 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 droplets that make up the dispersed phase are typically about 10 nm to 100 μm in diameter; i.e., the droplets may exceed the usual size limits of colloidal particles. If the dispersed phase is an organic material ("oil") and the continuous phase is water or an aqueous solution, the emulsion is called an oil / water (o / w) emulsion. If 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.

[0055] A substantially or completely "oil-free" emulsion is one that contains no continuous or dispersed oily phase, or contains an oily phase (continuous or dispersed) in such small amounts that it does not materially affect the properties of the emulsion.

[0056] Emulsions contain a continuous phase and a dispersed phase, with the boundaries between the phases being called "interfaces". Emulsions can have a cloudy appearance due to the many phase interfaces scattering the light that passes through the emulsion. When the rays are scattered in equal proportions, they appear white. If the emulsion is diluted, then the high-frequency and low-wavelength types of light will be scattered into more parts. For example, an emulsion of this type will appear blue ("Tyndall effect").

[0057] In the 1950s, the term "microemulsion" (ME) was widely used to describe multiphase systems consisting primarily of water, oil, surfactants, and alcohols. MEs are thermodynamically stable colloidal dispersions of micelles with particle sizes ranging from about 10 nm to 100 nm. MEs can form clear or transparent solutions that typically require simple mixing of the ingredients. MEs are low viscosity systems containing an aqueous phase, an oil phase, a surfactant, and a co-surfactant. MEs are micellar dispersions that typically require higher concentrations of surfactant loading than typical micellar solutions.

[0058] The term "nanoemulsion" (NE) is also a clear or transparent colloidal dispersion. However, in contrast to ME, NE is not thermodynamically stable and generally requires high shear processing to form.

[0059] "Micelles" are aggregates of molecules in colloidal solutions. In aqueous systems, they are organized structures formed by surfactants in water. Clear micellar solutions in oil-in-water aqueous dispersions typically 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 surround hydrophobic ingredients such as fragrances and oils and can form clear or transparent dispersions if appropriate surfactants and / or solvents are used at high enough concentrations.

[0060] An "emulsifier" is a substance that stabilizes an emulsion by increasing its kinetic stability. Emulsifiers are part of a broader class of compounds known as surfactants or "surface-active agents." Surfactants (emulsifiers) are typically amphipathic compounds, meaning 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 morphology, emulsifiers tend to have varying degrees of solubility in water or oil. Emulsifiers that are more soluble in water (and less soluble in oil) will generally form oil-in-water emulsions, while emulsifiers that are more soluble in oil (and less soluble in water) will form water-in-oil emulsions.

[0061] "Miscibility" is the property of two substances to completely mix to form a homogeneous solution. Typically, the term is used to describe liquid mixtures, but it can also be used for solids and gases. If two substances mix in all proportions or concentrations to form a solution, they are miscible. In other words, it doesn't matter whether you mix them in equal amounts or if one component is present in higher amounts than the other. If two substances cannot completely mix to form a solution, they are immiscible. When they combine, immiscible substances separate into layers or form an inhomogeneous mixture. Miscibility is the ability of a mixture (e.g., a mixture of two different liquids) to form a single phase within a specified range of temperature, pressure, and composition. 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 can demix if properly nucleated. If the mixture is thermodynamically unstable, it can demix by spontaneous decomposition (i.e., without nucleation) or by nucleation and growth (if properly nucleated).

[0062] "Solubility" generally refers to the degree to which a substance dissolves in a solvent to form 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 (completely miscible; for example, methanol and water) or partial (for example, oil and water are only slightly soluble). In general, "like dissolves like" (for example, aromatic hydrocarbons dissolve in each other, but not in water). Solubility is the ability of a solid, liquid, or gas 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, its 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 a saturated solution. When the addition of additional solute no longer increases the concentration of the solution, the solution is considered to be saturated. Depending on the substance, solubility varies greatly, from infinitely soluble (completely miscible) (such as ethanol dissolving in water) to sparingly soluble (such as silver chloride dissolving in water). The term "insoluble" is usually used for 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.

[0063] "Poorly Water-Soluble Compounds": The United States Pharmacopeia (USP) specifies the solubility of a drug as the part of solvent required to dissolve one part of solute. The solubility of a drug, including active and / or inactive ingredients, can be expressed in a variety of ways, such as weight percent, molar concentration, and mass molality. The USP lists the solubility of a drug as the number of milliliters of solvent required to dissolve 1 gram of solute and specifies descriptive terms in the summary provided below.

[0064]

[0065] The compounds used in the following examples meet the criteria of slightly soluble, very slightly soluble, and practically insoluble, which are collectively referred to as "poorly water-soluble" compounds.

[0066] Solubility table of example compounds in relation to the USP solubility definition.

[0067]

[0068]

[0069] The term "polyethylene glycol" or "PEG" refers to the compound H(OCH2CH2) nOH or a derivative thereof, wherein n is 2 to about 1,000 in the PEG chain. In various embodiments, the molecular weight of the PEG chain can be about 500 to about 200,000. In certain embodiments, the molecular weight of the PEG group can be 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 molecular weight of the PEG group can be about 4,000 or about 7,000. The PEG group can be terminated at its end with a protecting group such as an acetyl group or an alkyl group (such as a methyl or ethyl group). In a polymer, two or more ethylene glycol segments can form a polyethylene glycol ("PEG") chain. Typically, the number (n) will be much greater than two segments, such as 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 above values. In certain embodiments, n is from about 30 to about 40. In an exemplary embodiment, n is 40.

[0070] The molecular weight of PEG chain can be about 200g / mol to about 40,000g / mol. Some embodiments can have about 300g / mol to about 30,000g / mol or about 400g / mol to about 20,000g / mol PEG moieties. Some embodiments can have 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 PEG moieties, or any range between any two of the above values. PEG groups can be single-chain, double-chain, branched or cyclic or polycyclic groups. In some cases, high molecular weight PEG chains can be used to improve the solubility of block copolymers in coupling various types of water-insoluble drugs and / or molecules.

[0071] While the description and examples focus on topical application of emulsions containing poorly water soluble active ingredients, it can be readily seen that the present invention can be used as a platform for formulating and delivering poorly water soluble inactive ingredients and administering emulsions by routes other than topical (e.g., ocular, mucosal, intravenous, intramuscular, sublingual, and oral).

[0072] Emulsions, particularly microemulsions, miniemulsions and nanoemulsions, are advantageous for topical delivery of active (and / or inactive) ingredients to different layers of the epidermis and the body's systemic circulation. Conventional topical treatments (such as gels and creams) are often inefficient and poor in cosmetic and aesthetic appeal, which can result in poor patient compliance or adherence, while systemic treatments and phototherapy often produce significant adverse side effects. The small particle and droplet sizes present in nanoemulsion (about 5nm to 500nm) drug formulations can enhance the appearance, delivery and penetration of drugs through the epidermis and skin layers.

[0073] The art of formulating topical compositions to treat diseases, ailments or disorders through the skin requires the complex application of multiple scientific disciplines (e.g., chemistry, biology, physics, mathematics, and materials). A common challenge faced by formulators is how to best mix active ingredients with other (active or inactive) ingredients to provide an effective and easy-to-use composition. It has been determined through experimentation that the oil-free aqueous emulsions of the present invention can be used as a platform for solubilizing active (and inactive) ingredients that are poorly water soluble. The compositions and methods of use described herein facilitate the production of a variety of products in a multidisciplinary field.

[0074] The topical emulsion system described herein has no oil phase (substantially or completely) and can be formulated as a fine aqueous emulsion, a micro-aqueous emulsion or a nano-aqueous emulsion. It comprises:

[0075] (i) from about 2.5% to about 50% by weight of diethylene glycol monoethyl ether (DEGEE);

[0076] (ii) about 5% to about 20% by weight of polyethylene glycol (PEG:H(OCH2CH2)) of castor oil n OH) derivatives, wherein n is 2 to about 1000;

[0077] (iii) from about 60% to about 92% by weight water; and

[0078] (iv) from about 0.01% to about 2.0% by weight of a poorly water-soluble compound dispersed in a substantially or completely oil-free topical emulsion.

[0079] In one embodiment, n in the PEG chain is equal to about 30 to about 40. In certain embodiments, the PEG derivative of castor oil can be PEG 40 (n=40) hydrogenated castor oil (PEG 40HCO).

[0080] The emulsion system can be used as a formulation platform to produce nanoemulsions of active ingredients (e.g., flavonoids) without the presence of an oil phase in the emulsion. The emulsion platform can produce nanoparticles (and nanodroplets) that improve the appearance of the product and effectively deliver active (and / or inactive) ingredients locally, while solving the solubility problems inherent in poorly water-soluble compounds that adversely affect their bioavailability. The formulation platform can be used to prepare a composition that maintains transparency and solubility after further dilution with water without the need for an oil phase used in traditional fine, nano, and micro oil-in-water or water-in-oil emulsions. The formulation platform provides a wide range of applications for local delivery of poorly water-soluble compounds that cannot be effectively orally administered. The dissolved composition can be mixed into a matrix (such as a lotion or cream) to enhance the penetration and delivery properties of the compound.

[0081] The formulation according to the present invention provides an emulsion platform that can be used to manufacture products in many industries, such as pharmaceutical, cosmetic, personal care, industrial, food, etc. In the pharmaceutical field, it can be used to produce products for the treatment of various ailments and disorders, such as hair loss, psoriasis, cancer, inflammation, and pigmentary diseases such as vitiligo and melasma.

[0082] The emulsion platform can be designed to provide preventive benefits (e.g., UV protection, anti-aging protection, dietary supplements for the prevention and / or treatment of various medical problems, etc.) or absorb drugs that undergo high first-pass metabolism during oral or other delivery modes. It can also be used to encapsulate gene therapy products such as siRNA, cccDNA, mRNA, etc.

[0083] In an embodiment, the topical composition of the present invention including active ingredients may further include inactive ingredients, such as co-solvents, co-emulsifiers, cationic co-surfactants, ionic co-surfactants or non-ionic co-surfactants, stabilizers, thickeners, antioxidants, conditioners, moisturizers, emollients, penetration enhancers, preservatives, nutrients, fragrances, pigments, colorants, dispersants, antipruritics, antiperspirants, antipsoriatic agents, anti-seborrheic agents, anti-aging agents, anti-wrinkle agents, skin whitening agents, depigmenting agents, vitamins, nutrients, fragrances, preservatives, stabilizers or combinations thereof.

[0084] The composition may include one or more active ingredients. For example, the active ingredient may be a natural product, such as a flavonoid (such as a flavanol) or a polyphenol. Exemplary natural products include, but are not limited to, fisetin, trans-resveratrol, a milk thistle extract containing silymarin, quercetin, dihydroquercetin, curcumin (and / or turmeric), (-)-epigallocatechin gallate (EGCG), rutin, diosmin, an extract of schizonepeta tenuifolia, imatinib and imatinib mesylate. The active ingredient may be a hair growth promoter or an antibiotic, an antiseptic, an antifungal, an antibacterial, an anti-inflammatory, an analgesic, an antiviral, an anesthetic, an anticancer agent (e.g., imatinib or its mesylate) or an anti-acne agent.

[0085] Optionally, the composition can include "natural" or "essential" oils. In the pharmaceutical, food, personal care, skin care and cosmetic fields, natural oils have been studied and sold for various skin disorders and other ailments. Some examples include coconut oil, almond oil, grapeseed oil, olive oil, sunflower seed oil, argan oil, rosehip oil, jojoba oil, marula oil, tea tree oil and safflower oil. Similarly, essential oils are also the subject of various studies in these fields. The example of essential oils includes lavender oil, chamomile oil, sandalwood oil, sage oil, rosemary oil, frankincense oil, geranium oil, neroli oil, lemon oil, lemongrass oil, cinnamon oil, tea tree oil, peppermint oil, wintergreen oil, eucalyptus oil, patchouli oil, pomegranate oil, carrot seed oil, orange oil, ylang-ylang oil, rose oil, myrrh oil and jojoba oil.

[0086] Although both essential oils and natural oils come from plants, there are differences between the two categories. Essential oils are extracted from plants or leaves, roots, bark, and other aromatic parts of plants. These oils have a strong scent when evaporated. Therefore, essential oils are concentrated hydrophobic liquids containing volatile aromatic compounds from plants / botanicals. Due to their high potency, essential oils can cause irritation to the skin and are usually diluted with a carrier oil to alleviate this problem.

[0087] In contrast, natural oils are usually pressed from the fatty parts of plants or plant preparations, such as seeds, nuts, or kernels. Chemically, natural oils are triglycerides, in which glycerol 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 usually do not require the addition of a carrier oil for use.

[0088] In embodiments, topical compositions can be in the form of ointments, creams, emulsions, lotions, pastes, unguents, gels, tinctures, sunscreens, sprays or other topical dosage forms. Emulsions described herein can also include cleansers, emollients or aromatic compounds. Ointments, creams, lotions and unguents according to the present invention can also include waxes, alcohols or petroleum-based softeners.

[0089] Optionally, the gel according to the invention comprises vegetable oil, for example up to about 5% by weight of the total composition weight. The gel may also comprise water and / or a thickener. The thickener may be a natural polysaccharide, such as xanthan gum, carrageenan, alginate and / or cellulose gum.

[0090] Optionally, the paste according to the invention may contain aloe vera gel and / or beeswax.

[0091] Optionally, lotions according to the present invention may include cetyl alcohol, emulsifiers, fragrances, glycerin, petrolatum, dyes, one or more preservatives and / or stabilizers.

[0092] Optionally, the sunscreen composition according to the present invention may include a UV absorber or blocker, for example, in an amount of about 0.1% to about 10% by weight of the total composition weight. Exemplary UV absorbing compounds include, but are not limited to, benzone compounds, glyceryl PABA, roxamate, octocrylene, octyl methoxycinnamate, ethoxyethyl p-methoxycinnamate, trimethylcyclohexyl salicylate, ethylhexyl salicylate, triethanolamine salicylate, ecamsul, phenylbenzimidazole sulfonic acid, bis-ethylhexyloxyphenol methoxyphenyl triazine and bisoctrizole. Exemplary UV blocking compounds include, but are not limited to, zinc oxide and titanium dioxide.

[0093] The emulsion system of the present invention may include antibiotics, preservatives, antifungal agents, analgesics, antiviral agents and / or stabilizers. Some examples of these agents are listed below.

[0094] Antibiotics include, but are not limited to, ampicillin, bacampicillin, carindacillin, mezlocillin, piperacillin, ticarcillin, amoxicillin-clavulanic acid, ampicillin-sulbactam, penicillin, cloxacillin, dicloxacillin, methicillin, oxacillin, penicillin G, penicillin V, piperacillin-tazobactam, ticarcillin-clavulanic acid, nafcillin, procaine penicillin, cefadroxil, cefazolin, cephalexin, cephalothin, cefpirin, cephradine, cefaclor, cefamandole, cefonicid, cefotetan, cefoxitin, cefprozil, cefmetazole, cephalosporin 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 weight.

[0095] Preservatives 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 preservative in the topical formulation may be from about 0.01% to about 5% by weight of the total composition weight.

[0096] Antifungal agents include, but are not limited to, amphotericin B, candidatin, filipin, hamycin, natamycin, nystatin, chatomycin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole, sertaconazole nitrate, sulconazole, tioconazole, albaconazole, fluconazole, isavuconazole, itraconazole, posaconazole, rifoconazole, traconazole, voriconazole, abafungin, amorolfine, butenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox olamine, flucytosine, griseofulvin, chlorpropyl iodine, tolnaftate, undecylenic acid, gentian violet, and Peru balsam. In one embodiment, the amount of the antifungal agent in the topical formulation may be from about 0.01% to about 5% by weight of the total composition.

[0097] Analgesics include, but are not limited to, methyl salicylate, codeine, morphine, methadone, pethidine, buprenorphine, dihydromorphine, levorphanol, oxycodone, fentanyl, and nonsteroidal anti-inflammatory drugs. In one embodiment, the amount of analgesic in the topical formulation may be from about 0.01% to about 5% by weight of the total composition.

[0098] 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 may be from about 0.01% to about 5% by weight of the total composition.

[0099] Stabilizers include, but are not limited to, guar gum, xanthan gum, cellulose, hyaluronic acid, polyvinylpyrrolidone (PVP), alginate, chondroitin sulfate, poly-gamma-glutamic acid, gelatin, chitin, corn starch, and flour. In one embodiment, the amount of stabilizer in the topical formulation may be from about 0.25% (w / v) to about 2% (w / v).

[0100] The formulations can be prepared by conventional procedures known in the fields of pharmaceuticals, cosmetics, skin care, personal care, food and industrial chemistry. It is understood that the compositions described herein can be varied according to well-known techniques to accommodate different amounts and types of ingredients. In addition, the specific ingredients and proportions described herein are for illustrative purposes only. Depending on the desired properties of the dosage form of interest, the ingredients can be replaced with suitable equivalents or substitutes, and the proportions can vary.

[0101] Many active and inactive ingredients are characterized by low solubility in water and high solubility in oils or lipid mixtures. In topical applications, they do not easily adhere to or remain on the skin and have limited penetration properties. Some ingredients cannot be taken orally (due to ineffectiveness, toxicity issues, or other adverse side effects). Given these limitations, it is challenging for formulators to find the best (active and inactive) ingredients and optimal loading requirements to enhance the efficacy of the ingredients in the composition when taken orally or applied to and in contact with the skin of humans or animals. Other dosage forms (ocular, mucosal, intravenous, intramuscular, sublingual, etc.) need to address similar limitations.

[0102] Those skilled in the art of topical formulations can utilize the compositions and methods described herein to produce 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. Once in contact with the skin, the compositions of the present invention can effectively and efficiently deliver active and / or inactive ingredients and provide their beneficial properties to humans or animals in need.

[0103] The present invention includes a method for treating skin disorders and other types of ailments by applying a therapeutically effective amount of a composition of the present invention to the skin of a human or animal in need of treatment for a therapeutically effective amount of time. When the composition is in 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).

[0104] The skin is the largest organ that covers and protects the body. Skin disorders (aka diseases or ailments) are conditions that affect a person's skin. These disorders may cause rashes, inflammation, itching, skin damage, or other changes that are harmful to the skin. The causes of skin disorders may be due to genetic and / or lifestyle factors. Skin disorder treatments may include medications, creams, ointments, or lifestyle changes. Skin ailments include conditions that clog, irritate, or inflame the skin, leading to rashes or other changes in the skin's appearance. Some skin disorders are mild, while others can cause severe symptoms. Some of the more common skin disorders include:

[0105] Acne – Blockage of the skin follicles, which causes a buildup of oil, bacteria and dead skin in the pores.

[0106] Alopecia areata – small area of ​​hair loss.

[0107] Atopic dermatitis (eczema) – dry, itchy skin that becomes swollen, cracked, or scaly.

[0108] Psoriasis – scaly patches of skin that may swell or feel warm.

[0109] Raynaud's phenomenon - a periodic decrease in blood flow to the fingers, toes, or other body parts, causing numbness or changes in skin color.

[0110] Rosacea – redness, thickening of the skin, and pimples, usually on the face.

[0111] Skin cancer—the uncontrolled growth of abnormal skin cells.

[0112] Vitiligo – Patches of skin or hair contain less pigment than the surrounding skin or hair areas.

[0113] Melasma Patches of skin (brown or grayish-brown) that contain more pigment than the surrounding skin areas.

[0114] Varicose or spider veins — Enlarged, twisted, damaged veins, usually close to the surface of the skin on the legs.

[0115] Common causes of skin diseases include:

[0116] Bacteria are trapped in the pores or hair follicles.

[0117] Disorders that affect your thyroid, kidneys, or immune system.

[0118] Exposure to environmental triggers that cause inflammation, such as allergens (for example, poison ivy and poison oak) or contact with the skin of another person or animal.

[0119] Genetic disorders and / or hormonal disorders.

[0120] Fungus or parasites on the skin.

[0121] Medications, such as sulfasalazine, used to block inflammation in Crohn's disease, may cause an allergic rash, hives, or itching.

[0122] Viruses, such as human papillomavirus (HPV) or herpes simplex virus (HSV).

[0123] Diseases associated with diabetes, such as diabetic dermopathy, diabetic liponecrosis, diabetic bullae, and eruptive xanthomatosis.

[0124] Some examples shown below provide optimized topical oil-free aqueous emulsion systems for delivering fisetin, trans-resveratrol and / or milk thistle extract containing silymarin to promote hair growth. The formulations can be used to treat hair loss or promote hair growth for any other reason (e.g., growing hair on shaved areas of the body after a medical procedure).

[0125] Other examples shown below demonstrate the broad topical application of formulation technology:

[0126] Fisetin as a hair growth (and hair loss prevention) treatment.

[0127] Quercetin and (-)-epigallocatechin gallate (EGCG) are used to treat warts (such as common warts, plantar warts, and flat warts) and cold sores.

[0128] Curcumin is used to treat inflammation.

[0129] Salicylic acid is used to treat acne.

[0130] Goosegra (an herbal extract) is used to treat hair loss, eczema, or other skin conditions involving inflammation.

[0131] Dihydroquercetin is used for hair growth treatment and prevention of hair loss.

[0132] Rutin and trans-resveratrol, and optionally diosmin, for use in the treatment of varicose veins.

[0133] Imatinib or imatinib mesylate is used to treat pigmentary disorders (such as vitiligo and melasma).

[0134] Hair growth and hair loss prevention with the formulations of the present invention can occur in different ways. The formulations of the present invention can slow the rate of hair loss and / or promote the growth of new hair. It can repair / reactivate inactive hair follicles and / or grow new hair follicles. It can: (i) slow, prevent and / or reverse the miniaturization of hair follicles; (ii) increase blood flow around the hair follicles; (iii) stimulate the hair follicles to enter the growth phase; and / or (iv) extend the growth phase of the hair follicles. The formulations of the present invention can promote hair growth at a rate 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 hair density in the treated area by about 25%, about 50%, about 75%, about 100%, or any value in between.

[0135] The use of the formulation of the present invention can be used to regress the wart by peeling back the layers of the wart mass until the wart regresses. The formulation of the present 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. The dark spots or grainy texture areas that were once present are no longer visible. The regress rate of the wart can be about 25%, about 50%, about 75%, about 100%, or any value therebetween.

[0136] Common synthetic emulsifiers found in various products are polyethylene glycol (PEG:H(OCH2CH2) n PEG 40HCO is a PEG derivative of castor oil, wherein n is equal to 2 to about 1,000. For example, PEG 40 hydrogenated castor oil (PEG derivative of castor oil, abbreviated as PEG 40HCO) is used as a multifunctional emulsifier, surfactant, foam enhancer, emollient, detergent, solubilizer, thickener and / or cosolvent. It can be found in many commodities across different industries, such as medicines, cosmetics, food, skin care products and personal care products. PEG 40HCO does not have oiliness. However, it does have excellent emulsifying and solubilizing properties and is soluble in water and oil. It is particularly useful in aqueous preparations containing a large amount of aqueous phase, and combined with oil or other types of fats or lipids, water-in-oil nanoemulsions with clear and stable oil droplets can be prepared.

[0137] The following examples use PEG 40HCO to formulate aqueous emulsions without an oil phase. Although the examples employ PEG 40HCO as an emulsifier, the emulsions of the present invention may also be made with various other grades of polyoxyethylene hydrogenated castor oil, such as those having n in the PEG chain equal to about 30 to about 40.

[0138] Oleic acid is a fatty acid that occurs naturally in various animal and plant fats and oils. It is classified as a monounsaturated omega-9 fatty acid. Oleic acid is used as a component of many foods in the form of triglycerides. It is a component of the normal human diet and is found in animal fats and vegetable oils. The sodium salt of oleic acid is the main component of soap emulsifiers. It is also used as an emollient. Small amounts of oleic acid are often used as excipients in pharmaceuticals, or as an emulsifier or solubilizer in aerosol products. Oleic acid is widely used in the solution phase synthesis of nanoparticles as a kinetic knob to control the size and morphology of the nanoparticles.

[0139] A common cosolvent used to dissolve the compound is diethylene glycol monoethyl ether ["DEGEE", also known as 3,6-dioxa-1-octanol, 2-(2-ethoxyethoxy)ethanol, ethoxydiglycol or the trade name ]. It can be made by the condensation of ethylene oxide and ethanol followed by distillation. The presence of ether and alcohol functional groups in the molecule provides excellent solubilizing ability. DEGEE is an odorless liquid that is primarily used as a solubilizer and penetration enhancer in the manufacture of a variety of products, including soaps, dyes, cosmetics (such as vitamin C, dihydroxyacetone (DHA), and benzoyl peroxide), and other chemicals. It is also used in hair care products to promote longer-lasting, more even coloring. There are limitations to the use of DEGEE. DEGEE cannot be used as the sole solvent (100%) and typically needs to be formulated to a concentration of less than about 50% (preferably less than about 20%) in topical preparations. (For example, in the FDA Inactive Ingredient Database, there is one FDA-approved topical product that uses 49% DEGEE.) Although DEGEE does not have any oil or emulsifying properties, it is a useful co-solvent because it is miscible with water and some oils (such as almond oil or oleic acid).

[0140] Usually, water-in-oil (o / w) and water-in-oil (w / o) emulsions including oil, water, surfactant (or other emulsifier) ​​and cosolvent are prepared to improve the appearance, delivery and bioavailability of active compounds. DEGEE and PEG 40HCO have been used to prepare o / w emulsions with some compounds described herein. Most emulsions contain particles and droplets with an average diameter of >about 1 μm. However, miniemulsions, microemulsions and nanoemulsions according to the present invention can be designed to have a particle size and droplet size of about 100nm to 500nm. By appropriate formulations, highly stable emulsions with particles and droplets as small as several nanometers can be prepared.

[0141] As mentioned above, the formulations of the present invention can be used to treat a variety of skin disorders, such as alopecia (hair loss). Hair loss is common in humans and animals. There are many types of treatments that can reverse hair loss, or at least slow it down. Treatments include medications and surgery. Two popular medications are minoxidil and Finasteride Minoxidil is applied topically, and finasteride is taken orally. Minoxidil has several side effects (such as scalp irritation and unwanted hair growth on adjacent skin on the face and hands), and if a rash develops, use must be discontinued. Finasteride, taken orally, has rare side effects (such as decreased libido and sexual function, and an increased risk of prostate cancer) and is contraindicated in pregnant women because of the risk of hypospadias in a male fetus. Other oral medications include spironolactone and oral dutasteride Other topical products that have been studied are based on natural products that contain biotin, amino acids, curcumin, and caffeine as growth aids. Various other tinctures, serums, and blends of natural products have also been studied and are sometimes used to treat hair loss.

[0142] Despite the various types of hair loss treatments, their effectiveness and side effects are unsatisfactory. There is still a need for more effective hair loss products. Some hair growth studies in the literature have attempted to find new hair growth compounds that work through biological pathways different from those used by today's commercially available products (usually based on the classic androgenic alopecia model). Recent hair growth compounds include fisetin, trans-resveratrol, and silymarin (from milk thistle extract). These compounds are natural products that have been shown to promote growth through JAK / STAT and Wnt / β-catenin molecular pathways. However, despite the potential to promote growth, these compounds are reportedly not suitable for long-term application when applied in solution form (e.g., toxicity and side effects of ethanol and isoprene glycol). It is reported that topical delivery of fisetin with ethanol-based formulations is not feasible because it damages the hair, while topical delivery of trans-resveratrol with isoprene glycol formulations can block hair follicles. Therefore, these formulation carriers are generally unacceptable for commercially available products.

[0143] Emulsion technology has been applied to many active molecules, including fisetin, trans-resveratrol, and silymarin (from milk thistle extract). Fisetin, trans-resveratrol, and silymarin are active ingredients of natural products and have been the subject of many studies evaluating their hepatoprotective, antioxidant, anti-inflammatory, immunomodulatory, anticancer, cardioprotective, and hair growth properties. However, studies have shown that the oral bioavailability of all three compounds is low, thus limiting their effectiveness. Therefore, these three active compounds have not been administered orally, and various formulations have been developed to deliver them topically to the body. Several studies have shown that some of the compounds can be administered topically, mainly by using oil-in-water emulsion technology.

[0144] The structures of fisetin, trans-resveratrol, and silymarin are shown in Scheme 1 below.

[0145] Scheme 1. Chemical structures of fisetin, trans-resveratrol, and silymarin.

[0146]

[0148] Fisetin (3,3',4',7-tetrahydroxyflavone)(2-(3,4-dihydroxyphenyl)-3,7-dihydroxy-4H-1-benzopyran-4-one) (Scheme 1) is a bioactive flavonol (polyphenolic flavonoid) molecule present in many plants, fruits and vegetables (e.g., strawberries, apples, persimmons, grapes, onions and cucumbers) at concentrations ranging from 2 μg / g to 160 μg / g. Fisetin has been suggested to have antiproliferative, antiapoptotic and / or antioxidant activities. Literature reports that fisetin can be an effective chemopreventive / chemotherapeutic agent for several types of cancer and may have neuroprotective properties. However, the oral bioavailability of fisetin has been reported to be low, probably due to its poor water solubility (10.45 mcg / mL) and high lipophilicity (logP 3.2). In addition, fisetin has been shown to be highly metabolizable when taken orally or injected intravenously.

[0149] Resveratrol (5-[(E)-2-(4-hydroxyphenyl)ethene-1-yl]benzene-1,3-diol) (Scheme 1) is a natural polyphenolic stilbene compound found in a variety of plants, including many foods such as blueberries, mulberries, raspberries, grapes, red wine, and peanuts. It exists as two isomers, cis-resveratrol and trans-resveratrol. The trans-isomer is reported to be the more biologically active compound. Trans-resveratrol is classified as a phytoalexin and can be produced in response to fungal attack or certain types of stress, including trauma and UV irradiation. Trans-resveratrol has been studied for its potential therapeutic benefits in the treatment or prevention of cancer, heart disease, neurodegeneration, and inflammation. Trans-resveratrol is typically isolated from red wine / grape skin extracts or the plant Polygonum cuspidatum. However, it has low oral bioavailability and has limited utility as a human therapeutic. The bioavailability of trans-resveratrol is approximately 0.5%, probably due to extensive hepatic glucuronidation and sulfation. The feasibility of oral delivery of trans-resveratrol is questionable due to its low water solubility and short half-life (approximately 15 minutes).

[0150] Silybin (Scheme 1) is a flavonolignan extracted from the plant Silybum marianum (L.). It consists of a mixture of isomers of seven flavonolignans - silybin A, silybin B, isosilybin A, isosilybin B, silybin A, silybin B and silybinin - and a flavonoid compound - silybin. Silybin, also known as silibinin, has an 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 a variety of pharmacological properties, such as hepatoprotective, antioxidant, anti-inflammatory, anticancer, antifibrotic, and cardioprotective activities. Although clinical trials have shown that silymarin is nontoxic to humans at high doses (> approximately 1500 mg / day), pharmacokinetic studies have shown that the molecule is poorly absorbed, rapidly metabolized, and ultimately has low oral bioavailability.

[0151] There are many examples of oil-in-water miniemulsions, microemulsions, and nanoemulsions in the literature. See, for example, U.S. Pat. Nos. 10,918,606 and 10,736,842, and U.S. Pat.

[0152] Nos. 2021 / 0330598, 2021 / 077396, 2021 / 0046087, and 2018 / 0071390, the entire contents of which are incorporated herein by reference. Oil-in-water emulsions have been studied with fisetin, trans-resveratrol, and silymarin, as well as other active compounds such as quercetin or dihydroquercetin (a flavonoid compound belonging to the same class of compounds as fisetin, silymarin, and silybin), carvedilol, nitrendipine, vinpocetine, curcumin, (-)-epigallocatechin gallate (a polyphenol abbreviated as EGCG), and salicylic acid.

[0153] The molecular structures of quercetin, curcumin, (-)-epigallocatechin gallate, salicylic acid, and rutin are shown in Scheme 2 below.

[0154] Scheme 2. Quercetin, dihydroquercetin, curcumin, (-)-epigallocatechin gallate, salicylic acid, and rutin.

[0155]

[0156] (-)-Epigallocatechin gallate (EGCG)

[0157]

[0158] Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyran-4-one) and dihydroquercetin are plant pigments flavonoids (flavonols) (Scheme 2). They are potent antioxidants found in many plants and foods (e.g., red wine, onions, asparagus, broccoli, buckwheat, green tea, grapes, apples, cherries, berries, and citrus fruits). Quercetin has been reported to have protective abilities against tissue damage caused by various drug toxicities and has antioxidant, anti-inflammatory, antibacterial, and antiviral properties that may help reduce swelling, kill cancer cells, control blood sugar, and prevent heart disease. It has been used as a drug to prevent oxidative stress diseases (cardiovascular, bronchopulmonary, etc.). Dihydroquercetin has been reported to be more effective and more bioavailable than quercetin.

[0159] 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 (Tumeric) and other species of the Curcuma genus. It has been the subject of intensive research for its various activities (e.g., anti-inflammatory, anti-cancer, etc.) and can be found in many oral herbal supplements. Curcumin may help control exercise-induced inflammation and muscle soreness, thereby improving recovery and performance in active individuals. Oral administration of curcumin is generally not associated with health benefits due to its low bioavailability, which appears to be primarily due to poor absorption, rapid metabolism, and rapid elimination of turmeric. Curcumin coated with turmeric essential oil (ETO) was approximately 7 to 10 times more bioavailable and retained longer in the systemic circulation than standard curcumin.

[0160] (-)-Epigallocatechin 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 catechin. EGCG is a polyphenol (flavanol). It is the most abundant catechin in green tea. It has been studied for its potential to affect human health and disease due to its antibacterial, antiviral, and anticancer properties. However, when taken orally, EGCG is poorly absorbed, even at intakes equivalent to 8 to 16 cups of green tea per day. After ingestion, EGCG blood levels typically peak within 1.7 hours. The plasma absorption half-life of EGCG is approximately 5 hours, but most of the unchanged EGCG is excreted into the urine over a period ranging from almost immediately to about 8 hours.

[0161] Salicylic acid (2-hydroxybenzoic acid) belongs to a class of drugs called salicylates (Scheme 2). When applied to the skin, salicylic acid works by helping the skin shed dead cells from the top layer and reducing redness (inflammation). This application can reduce skin disorders, such as acne and warts, and speed up the healing of the skin by boosting the body's immune system.

[0162] 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-[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxybenzopyran-4-one) (Scheme 2), also known as rutin, quercetin-3-rutin, and sophoroside, is a glycoside combining the flavonol quercetin and the disaccharide rutinose. It is a flavonoid found in a variety of plants, fruits, and vegetables (e.g., citrus flavonoids found in buckwheat). Rutin may have antioxidant and anti-inflammatory effects. It has been studied as a potential drug for preventing cancer and other diseases. Rutin is often used for autism, skin aging, exercise-induced respiratory infections, and other purposes, but there is little scientific evidence to support its effectiveness.

[0163] Kshavak / Sneezewort is a plant leaf herb that has been used in traditional Chinese medicine for centuries to treat respiratory diseases. Twelve common components have been identified in the ethanol extract of Kshavak, including flavonoids and their glycosides, phenolic and polyphenolic acids, and sesquiterpene lactones. Brevibrin A, a sesquiterpene lactone isolated from Kshavak, has been shown to inhibit Janus kinase 3 (JAK3), a cellular pathway involved in hair loss and cancer treatment.

[0164] Other active ingredients, such as diosmin, imatinib and imatinib mesylate, can be used in the aqueous emulsions described herein. Their molecular structures are shown in Scheme 3 below.

[0165] Scheme 3. Chemical structures of diosmin, imatinib and imatinib mesylate.

[0166] Diosmin

[0167] Imatinib

[0168] Imatinib mesylate

[0169] 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-methyltetrahydropyran-2-yl]oxymethyl]tetrahydropyran-2-yl]oxybenzopyran-4-one) (Scheme 3) is a disaccharide derivative consisting of diosmin partially substituted at position 7 by 6-O-(α-L-rhamnopyranosyl)-β-D-glucopyranose via a glycosidic bond. It has antioxidant and anti-inflammatory effects. It is a glycosylflavonoid, a rutin, a disaccharide derivative, a monomethoxyflavonoid, and a dihydroxyflavanone. It is functionally related to diosmin.

[0170] Imatinib (4-[(4-methylpiperazin-1-yl)methyl]-N-(4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2-yl]amino}phenyl)benzamide) and its mesylate (Scheme 3) are 2-phenylaminopyrimidine derivatives that are specific inhibitors of a variety of tyrosine kinases. They are small molecule inhibitors of a variety of receptor tyrosine kinases, such as CSF1R, ABL, c-KIT, FLT3, and PDGFR-β. Imatinib mesylate is commercially available under the trade names Gleevec and Glivec, etc., and is used as an oral targeted therapy for the treatment of cancer.

[0171] The above compounds were formulated using the emulsion systems of the present invention and the topical compositions were applied to the skin of human subjects to test for various diseases.

[0172] The novel compositions described herein include poorly water-soluble compounds in a water-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 can be used topically and in other modes of application to treat various skin disorders (e.g., alopecia, plantar warts, cold sores, etc.) and other types of diseases or ailments.

[0173] The following examples are intended to illustrate the present invention and should not be construed as limiting the scope of the present invention. It will be readily appreciated by those skilled in the art that these examples provide other ways in which the present invention may be implemented. It should be understood that many variations and modifications may be made while remaining within the scope of the present invention.

[0174] Example

[0175] Example 1. Formulation of a topical composition comprising fisetin, trans-resveratrol and milk thistle (including silymarin)

[0176] The present study aims to formulate active ingredients fisetin, trans-resveratrol and milk thistle extract (including silymarin) into a combination product, which can be used as a topical composition for preventing hair loss and / or promoting hair growth. The study provides a stable and transparent oil-free aqueous nanoemulsion, which includes active ingredients polyethylene glycol (PEG) 40 hydrogenated castor oil (PEG40HCO), diethylene glycol monoethyl ether (DEGEE) and water, wherein the active ingredients are dispersed in the oil-free topical emulsion.

[0177] DEGEE is an odorless, liquid, water-miscible cosolvent that improves the solubility and penetration of compounds when applied to human or animal skin.

[0178] PEG 40HCO is a waxy, viscous, water-miscible liquid emulsifier. PEG 40HCO by itself was not effective in dissolving fisetin, trans-resveratrol, or milk thistle extract (including silymarin) powders. It did not adequately wet the compound powders and was too viscous to be used as a solvent alone. However, when PEG 40HCO was added to a DEGEE mixture containing fisetin, trans-resveratrol, and milk thistle extract (including silymarin), all three compounds were successfully dissolved.

[0179] In a solubility screening panel evaluating surfactants and other emulsifiers for topical application, it was found that either fisetin, trans-resveratrol or milk thistle extract (including silymarin) were soluble in DEGEE. The initial goal was to find a miscible oil suitable for hair application, such as argan oil, sesame oil, sunflower oil, fractionated coconut oil and grapeseed oil. None of the oils evaluated were miscible with DEGEE, and the resulting mixture showed a clear separation of DEGEE and the oil phase. The next step was to evaluate oil-soluble emulsifiers such as glyceryl monooleate, sorbitan oleate, dodecyl oleate and lauryl sulfate. It was found that glyceryl monooleate increased the miscibility of DEGEE with argan oil. However, when the mixture was diluted with water, a suspension was formed and the active ingredient precipitated out of the solution. It is known that oleic acid (a fatty acid) is miscible with DEGEE, but it is a non-comedogenic fatty acid, which makes it unsuitable for long-term topical application preparations. Oleic acid was evaluated with a mixture of sorbitan laurate, polyglyceryl-4 laurate, and dilauryl citrate. This formulation made a miscible mixture with fisetin, trans-resveratrol, or silybum marianum dissolved in DEGEE. However, dilution of the mixture with water produced a suspension, and after about an hour, the solids precipitated out again.

[0180] At this point, the goal of the study changed. Rather than further evaluate the oil phase mixture, 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 out. However, the active ingredient did not precipitate and the diluted solution retained a clear yellow appearance and remained stable. Without being bound by any particular theory, it can be speculated that this result indicates that either a nanoemulsion was formed or that PEG 40HCO somehow produced a supersaturated solution. The result was unexpected because previous formulations that included an oil (or fatty acid) component would produce an oil-in-water emulsion, but this formulation lacked an oil phase as a component of the mixture, but produced a stable, clear aqueous emulsion.

[0181] In view of the unexpected result of forming an oil-free aqueous emulsion, the following formulations (AH) were prepared:

[0182] A—Dissolve about 0.15% of Fisetin in DEGEE and then dilute with water in a 1:1 ratio.

[0183] B—Dissolve approximately 0.15% trans-resveratrol in DEGEE and then dilute with water at a 1:1 ratio.

[0184] C—Dissolve approximately 0.25% of milk thistle extract (containing silymarin) in DEGEE and then dilute with water in a 1:1 ratio.

[0185] 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 40HCO), about 20% diethylene glycol monoethyl ether (DEGEE), and about 69.45% purified water.

[0186] 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 40HCO), about 10% diethylene glycol monoethyl ether (DEGEE), and about 84.725% purified water. (Formulation D is further diluted)

[0187] 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 40HCO), about 10% diethylene glycol monoethyl ether (DEGEE), and about 84.45% purified water.

[0188] All mixtures (Formulations AF) were stable and clear.

[0189] 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 40HCO), about 10% diethylene glycol monoethyl ether (DEGEE), and about 79.45% purified water.

[0190] Formulation G remained stable and transparent, and the nanoparticles were analyzed (see Table I below). Nanoparticle tracking technology observed that the nanoparticles in the mixture had a d50 particle size of about 119.5 nm and a number weighted average particle size of about 125.4 nm. This result was unexpected for the mixture. Those skilled in the art of formulation development would have expected that in the absence of an oil phase, the active ingredient in the PEG 40HCO and DEGEE mixture would precipitate when diluted with water.

[0191] Table I

[0192] Nanoparticle Analysis Data Summary

[0193]

[0194]

[0195] H—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 40HCO), about 5% diethylene glycol monoethyl ether (DEGEE), and about 89.45% purified water. Formulation H remained transparent and stable, and nanoparticle tracking technology observed that the d50 particle size of the nanoparticles in the mixture was about 37.8 nm, and the number-weighted average particle size was about 36.4 nm (see Table II below). These results indicate that the particle size (and droplet size) can be designed by the formulation composition. Since smaller particle size (and droplet size) should theoretically enhance the appearance and permeability of the formulation, it is assumed that Formulation H may be more suitable for administration as a combination product than Formulation G.

[0196] Table II

[0197] Nanoparticle Analysis Data Summary

[0198]

[0199] Nano-sized particles were measured using the Malvern NanoSight NS300. The NanoSight NS300 uses the Nanoparticle Tracking Analysis (NTA) technique. This technique exploits the properties of light scattering and Brownian motion to obtain size distribution and concentration measurements of particles in liquid suspensions. A laser beam passes through the sample chamber and particles suspended in the path of this beam scatter light in such a way that they can be easily observed through a 20x magnification microscope mounted with a camera. The camera runs at 30 frames per second (fps) capturing a video file of the movement of particles 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 by the user-friendly software interface.

[0200] Next the following Formulation IM was prepared.

[0201] A base composition comprising about 0.15% fisetin, about 0.15% trans-resveratrol, about 0.25% milk thistle extract (about 0.2% silymarin), about 10% diethylene glycol monoethyl ether (DEGEE), and the following amounts of PEG 40 hydrogenated castor oil (PEG 40HCO):

[0202] I——About 1% PEG 40HCO.

[0203] J——About 2.5% PEG 40HCO.

[0204] K——about 5% PEG 40HCO.

[0205] L——about 7.5% PEG 40HCO.

[0206] M——about 10% PEG 40HCO.

[0207] Each of the formulations IM was diluted to 100% with purified water. The experiment showed that formulations I and J (containing about 1% and about 2.5% PEG 40HCO, respectively) did not form a nanoemulsion, and solid precipitation of the active ingredient was observed in both formulations. In contrast, formulation KM (containing about 5%, about 7.5%, and about 10% PEG 40HCO) remained transparent and stable.

[0208] Example 2. Formulation of a composition comprising fisetin

[0209] The formulation was prepared using fisetin as the sole active ingredient. The concentration of fisetin in the formulation was increased to about 0.25% w / w fisetin, and the formulation contained about 2.6% DEGEE, about 8.0% PEG 40HCO, and about 89.15% purified water.

[0210] The formulation is prepared by dispensing the desired amount of Fisetin and adding it to a container of appropriate size. The desired amount of DEGEE is added along with a magnetic stir bar and the mixture is stirred until the solid is dissolved. PEG 40HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the Fisetin / DEGEE mixture and the three ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while stirring to produce a clear nanoemulsion.

[0211] The formulation containing a stable nanoemulsion concentration of about 0.25% w / w fisetin (2.5 mg / mL) increased the water solubility of fisetin by approximately 250-fold over the reported concentration of about 0.01 mg / mL.

[0212] Another formulation was prepared using a conditioning agent base as the diluent instead of water. The detailed breakdown of the formulations (approximately % w / w) is summarized in Table III below.

[0213] Table III

[0214]

[0215]

[0216] The formulations produce stable and transparent nanoemulsions. They can be used for various ailments through different modes of administration, such as topical compositions for promoting hair growth.

[0217] Example 3. Topical application of a formulation comprising fisetin to promote hair growth

[0218] The formulation of Example 2 was evaluated on the scalp of human males exhibiting hair thinning (alopecia). New hair growth was observed after four weeks of application of a product containing about 0.25% fisetin, about 2.6% DEGEE, about 7.5% PEG 40HCO, and about 89.65% water. The formulation was applied once daily after showering and towel drying the hair. The formulation was applied to the scalp with a dropper, gently massaged, and air dried. Approximately 1 mL of product was used daily. After four weeks of treatment, the male subjects had their hair cut and hair growth evaluated by photographs. The before and after treatment photographs are as follows: Figure 1 After four weeks of treatment, hair growth was observed in the crown of the scalp. The increase in the concentration of hair present in the treated area appeared to be greater than about 25%.

[0219] Example 4. Formulation of a composition containing trans-resveratrol

[0220] The formulation was prepared using trans-resveratrol as the sole active ingredient. The concentrations of the ingredients in the formulation were about 0.15% w / w trans-resveratrol, about 2.6% DEGEE, about 7.5% PEG 40HCO, and about 89.75% purified water.

[0221] The formulation is prepared by dispensing the desired amount of trans-resveratrol and adding it to a container of appropriate size. The desired amount of DEGEE is added along with a magnetic stir bar and stirred until the solid is dissolved. PEG 40HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the trans-resveratrol and DEGEE mixture, and the three ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while stirring to produce a clear nanoemulsion.

[0222] The formulation containing a stable nanoemulsion concentration of about 0.15% w / w trans-resveratrol (about 1.5 mg / mL) has about a 50-fold increase in water solubility over the reported trans-resveratrol concentration of about 0.03 mg / mL.

[0223] The preparation can be used for various ailments through different modes of administration, such as a topical composition for promoting hair growth.

[0224] Example 5. Formulation of a composition comprising quercetin

[0225] The formulation was prepared using quercetin as the sole active ingredient. The formulation was prepared by dispensing the desired amount of quercetin and adding it to a container of appropriate size. The desired amount of DEGEE was added along with a magnetic stir bar and the mixture was stirred until the solid was dissolved. PEG 40HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to > approximately 50°C and added to the quercetin and DEGEE mixture and the three ingredients were mixed until homogeneous. The desired amount of purified water was added to the mixture while stirring to produce a clear nanoemulsion.

[0226] The following observations were made for each composition:

[0227] • About 0.5% quercetin, about 2.6% DEGEE, about 8.0% PEG 40HCO, and about 88.9% water.

[0228] After 6 hours a solid precipitated out.

[0229] • About 0.5% quercetin, about 5.0% DEGEE, about 8.0% PEG 40HCO, and about 86.5% water.

[0230] Precipitated after 11 hours.

[0231] • About 0.5% quercetin, about 0.15% fisetin, about 5.0% DEGEE, about 8.0% PEG 40HCO, and about 86.35% water.

[0232] • Precipitated out after 11 hours, but the solids were 80% less than quercetin alone.

[0233] • About 0.05% quercetin, about 5.0% DEGEE, about 10.0% PEG 40HCO, and about 84.95% water.

[0234] Maintain stable and transparent nanoemulsion.

[0235] A stable nanoemulsion concentration formulation containing about 0.5% w / w quercetin (5 mg / mL) increased the water solubility of about 0.002 mg / mL quercetin by about 2,500-fold, although only for a few hours. A stable, transparent nanoemulsion formulation containing about 0.05% w / w quercetin (0.5 mg / mL) increased the water solubility of quercetin by about 250-fold over the reported water solubility of quercetin.

[0236] The preparation can be used for various ailments through different modes of administration, such as a topical composition for promoting hair growth.

[0237] Example 6. Formulation of a composition comprising curcumin

[0238] Formulations were prepared using curcumin as the sole active ingredient. The concentrations of the components in one formulation were about 0.5% w / w curcumin, about 2.6% DEGEE, about 8.0% PEG 40HCO, and about 88.9% purified water. Another formulation was prepared with about 0.03% w / w curcumin, about 2.6% DEGEE, about 7.5% PEG 40HCO, and about 89.87% purified water.

[0239] The formulations were prepared by dispensing the required amount of curcumin and adding it to a container of suitable size. The required amount of DEGEE was added along with a magnetic stir bar and the mixture was stirred until the solids dissolved. PEG 40HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It was heated to > approximately 50°C and added to the curcumin and DEGEE mixture and the three ingredients were mixed until homogeneous. The required amount of purified water was added to the mixture while 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 transparent, showing no signs of precipitation.

[0240] A formulation containing a stable nanoemulsion concentration of about 0.5% w / w curcumin (about 5 mg / mL) showed an increase in water solubility of about 83,000 times over the reported water solubility of about 0.0006 mg / mL curcumin, although only for a few hours. A formulation containing a stable nanoemulsion concentration of about 0.03% w / w curcumin (about 0.3 mg / mL) showed an increase in water solubility of about 500 times over the reported water solubility of curcumin.

[0241] Similar formulations can be prepared in the same manner using turmeric or turmeric / curcumin combinations. The formulations can be used for various ailments through different modes of administration, such as topical compositions for treating inflammation.

[0242] Example 7. Formulation of a composition comprising (-)-epigallocatechin gallate (EGCG)

[0243] The formulation was prepared using EGCG as the only active ingredient. The concentrations of the ingredients in the formulation were about 1.0% w / w EGCG, about 5.0% DEGEE, about 10.0% PEG 40HCO, and about 84.0% purified water.

[0244] The formulation is prepared by dispensing the desired amount of EGCG and adding it to a container of appropriate size. The desired amount of DEGEE is added along with a magnetic stir bar and stirred until the solid is dissolved. PEG 40HCO is a semisolid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the EGCG / DEGEE mixture, and the three ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while stirring to produce a clear nanoemulsion.

[0245] Formulations containing a stable nanoemulsion concentration of about 1.0% w / w EGCG (about 10 mg / mL) exhibited approximately a 2-fold increase in aqueous solubility over the reported EGCG concentration of about 5 mg / mL.

[0246] The preparation can be used for various ailments through different modes of administration, for example, as a topical composition for treating skin disorders.

[0247] Example 8. Formulation of a composition comprising quercetin and EGCG

[0248] Formulations were prepared using EGCG and quercetin as active ingredients. The concentration of each ingredient in one formulation was about 2.0% w / w EGCG, about 0.1% quercetin, about 5.0% DEGEE, about 10.0% PEG 40HCO, and about 82.9% purified water. The concentration of each ingredient in another formulation was about 1.0% w / w EGCG, about 0.05% quercetin, about 2.5% DEGEE, about 5.0% PEG 40HCO, and about 91.45% purified water.

[0249] The formulation was prepared by dispensing the desired amounts of EGCG and quercetin and adding them to a container of appropriate size. The desired amount of DEGEE was added to the EGCG / quercetin mixture along with a magnetic stir bar and the mixture was stirred until the solids dissolved. PEG 40HCO is a semisolid at room temperature with a melting point of approximately 50°C. It was heated to > approximately 50°C and added to the EGCG / quercetin / DEGEE mixture and the four ingredients were mixed until uniform. The desired amount of purified water was added to the mixture while stirring to produce a clear nanoemulsion.

[0250] The preparation can be used for various ailments through different modes of administration, for example, as a topical composition for treating skin disorders.

[0251] Example 9. Topical administration of a formulation comprising quercetin and EGCG

[0252] Warts are a skin infection caused by a virus, the human papillomavirus (HPV). They can appear anywhere on the body and are usually raised, rough, skin-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 different appearance. Lesions on the soles of the feet may be called plantar warts. This is defined as an ingrown wart that can be caused by the pressure that the feet are subjected to on a daily basis. It can cause severe pain and discomfort.

[0253] Salicylic acid, up to about 40% concentration, is a commercially available wart treatment. Salicylic acid can be applied in layers to peel the skin and remove the wart over time. This acid also irritates (burns) the wart area, prompting the immune system to respond to the virus. However, it is slow to work and requires frequent applications for up to about 12 weeks to effectively treat skin containing the HPV virus. Wart removal via liquid nitrogen cryotherapy is another favorable option for many patients, with a cure rate of about 50% to 70% after three or four treatments.

[0254] A formulation containing EGCG and quercetin was evaluated as an antiviral treatment for several plantar warts present on the soles of the left and right feet of men. Warts were treated with a product containing about 0.1% quercetin, about 2.0% EGCG, about 5% DEGEE, and about 10% PEG40HCO in an aqueous system. The formulation was applied to the affected area (where the warts were located) twice a day, once after a shower in the morning and once before going to bed. The formulation was applied to the affected area by a cotton swab and allowed to dry.

[0255] Regression of warts was assessed by photographs taken approximately four weeks after treatment. Warts on the foot of a male subject were painful when standing or walking. The pain was substantially resolved within two days of applying the product. The viral roots of a wart on the left foot fell off approximately two weeks after applying the product. The viral roots of two warts on the right foot fell off approximately four weeks after applying the product. Figure 2 a and 2b (left foot) and Figure 3 a and 3b (right foot) show photographs taken approximately four weeks before and after treatment, respectively, showing that both feet were free of viral wart masses after treatment. Figure 4 4a and 4b show the removal of a wart from a treated wart on a human male's foot, and pictures showing the virus and root of the wart, respectively. The results for the EGCG / Quercetin formulation were surprising, indicating that the formulation could be used as an antiviral treatment for warts. This also suggests that the formulation is equally effective in treating cold sores.

[0256] Example 10. Formulation of a composition comprising salicylic acid

[0257] The formulation was prepared using salicylic acid as the sole active ingredient. The concentrations of the ingredients in the formulation were about 0.5% w / w salicylic acid, about 5.0% DEGEE, about 10.0% PEG 40HCO, and about 84.5% purified water.

[0258] The formulation is prepared by dispensing the required amount of salicylic acid and adding it to a container of appropriate size. The required amount of DEGEE is added along with a magnetic stir bar and the mixture is stirred until the solids are dissolved. PEG 40HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the salicylic acid / DEGEE mixture and the three ingredients are mixed until uniform. The required amount of purified water is added to the mixture while stirring to produce a clear nanoemulsion.

[0259] Formulations containing a stable nanoemulsion concentration of about 0.5% w / w salicylic acid (about 5 mg / mL) increased the water solubility by about 2-fold over the reported salicylic acid concentration of about 2.48 mg / mL.

[0260] The preparation can be used for various ailments through different modes of administration, for example, as a topical composition for treating skin disorders.

[0261] Example 11. Formulation of a composition comprising milk thistle (comprising silymarin)

[0262] The formulation was prepared 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 40HCO, and about 89.65% purified water.

[0263] The formulation is prepared by dispensing the desired amount of milk thistle and adding it to a container of appropriate size. The desired amount of DEGEE is added along with a magnetic stir bar and the mixture is stirred until the solids are dissolved. PEG 40HCO is a semi-solid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the milk thistle / DEGEE mixture and the three ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while stirring to produce a stable, transparent nanoemulsion.

[0264] The formulation containing a stable nanoemulsion concentration of about 0.2% w / w silymarin (2 mg / mL) increased the water solubility of silymarin by about 5-fold over the reported concentration of about 0.4 mg / mL.

[0265] The preparation can be used for various ailments through different modes of administration, such as topical compositions for promoting hair growth, vitiligo and melasma.

[0266] Example 12. Formulation of a composition comprising an extract of Herba Lysimachiae

[0267] Formulations were prepared using Herba Eupatoriae extract as the sole active ingredient, and the results showed that the herbal active ingredients were extracted with DEGEE. The dried Herba Eupatoriae was ground in a coffee grinder with a blade to produce a fine powder and added to a container of suitable size. The required amount of DEGEE was added to the ground powder along with a magnetic stirring bar at an extraction ratio of approximately 4:1, and the mixture was stirred until the solids dissolved. The resulting liquid mixture was stirred on a magnetic stirring plate for approximately 6 hours. The liquid was collected in a syringe and then filtered through a 1.4 μm glass syringe filter. The dark green, stable and transparent Herba Eupatoriae extract / DEGEE mixture was collected.

[0268] PEG 40HCO is a semisolid at room temperature with a melting point of approximately 50°C. It is heated to > about 50°C and added to the scutellaria extract / DEGEE mixture and the three ingredients are mixed on a magnetic stir plate until homogeneous. The desired amount of purified water is added to the mixture while stirring to produce a clear nanoemulsion. The concentrations of the components in the nanoemulsion formulation are approximately 3.0% DEGEE extract mixture, approximately 7.5% PEG 40HCO, and approximately 89.5% purified water. Scutellaria extract

[0269] / DEGEE / PEG 40HCO nanoemulsion is stable and transparent.

[0270] The scutellaria extract / DEGEE mixture and the scutellaria extract / DGEE / PEG 40HCO nanoemulsion were diluted with water at a ratio of about 1:1. However, when water was added to the scutellaria extract / DEGEE mixture, the components soluble in DEGEE precipitated out of the solution, forming a turbid suspension. However, the components in the scutellaria extract / DEGEE / PEG40HCO nanoemulsion remained stable and transparent.

[0271] Nanoemulsion formulations can be used for various ailments through different modes of administration, such as topical compositions for promoting hair growth.

[0272] Example 13. Formulation of Compositions Containing Dihydroquercetin

[0273] The preparation was prepared using dihydroquercetin as an active ingredient. The concentrations of the ingredients in the preparation were about 0.1% w / w dihydroquercetin, about 2.6% DEGEE, about 7.5% PEG 40HCO, about 88.8% purified water, and about 1.0% preservative.

[0274] The formulation is prepared by dispensing the desired amount of dihydroquercetin and adding it to a container of appropriate size. The desired amount of DEGEE is added along with a magnetic stir bar and the mixture is stirred until the solid is dissolved. PEG 40HCO is a semisolid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the dihydroquercetin / DEGEE mixture and the three ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while stirring to produce a clear nanoemulsion, followed by the addition of a preservative.

[0275] The formulation can be used for various ailments through different modes of administration, such as a topical composition for promoting hair growth or treating skin disorders.

[0276] Example 14. Formulation of a composition comprising rutin and trans-resveratrol

[0277] The preparation is prepared using rutin and trans-resveratrol as active ingredients. The concentration of each ingredient in the preparation is 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.

[0278] The formulation is prepared by dispensing the desired amounts of rutin and resveratrol and adding them to a container of suitable size. The desired amount of DEGEE is added to the container along with a magnetic stir bar and the mixture is stirred until the solids are dissolved. PEG40HCO is a semisolid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the rutin / trans-resveratrol / DEGEE mixture and the ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while stirring to produce a clear nanoemulsion, followed by the addition of preservatives and xanthan gum.

[0279] The preparation can be used for various ailments by different modes of administration, for example, a topical composition for treating varicose veins.

[0280] Example 15. Formulation of a topical composition containing imatinib (prediction drug)

[0281] The formulation can be prepared using imatinib free base as an active ingredient. The concentration of each ingredient in the formulation is about 0.5% w / w imatinib, about 2.6% DEGEE, about 7.5% PEG 40HCO, about 88.4% purified water and about 1.0% preservative.

[0282] The formulation is prepared by dispensing the desired amount of imatinib and adding it to a container of appropriate size. The desired amount of DEGEE is added to the container along with a magnetic stir bar and the mixture is stirred until the solid is dissolved. PEG 40HCO is a semisolid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the imatinib / DEGEE mixture and the three ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while 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.

[0283] Example 16. Formulation of a topical composition containing imatinib mesylate (precursor drug)

[0284] The preparation can be prepared using imatinib mesylate as an active ingredient. The concentration of each ingredient in the preparation is about 0.5% w / w imatinib mesylate, about 2.6% DEGEE, about 7.5% PEG 40HCO, about 88.4% purified water and about 1.0% preservative.

[0285] The formulation is prepared by dispensing the desired amount of imatinib mesylate and adding it to a container of appropriate size. The desired amount of DEGEE is added to the container along with a magnetic stir bar and the mixture is stirred until the solid is dissolved. PEG 40HCO is a semisolid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the imatinib mesylate / DEGEE mixture and the three ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while 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.

[0286] Example 17. Formulation of a topical composition comprising rutin, trans-resveratrol and diosmin (predator)

[0287] The preparation can be prepared using rutin, trans-resveratrol and diosmin as active ingredients. The concentration of each ingredient in the preparation is about 0.05% w / w rutin, about 0.15% resveratrol, about 2.6% DEGEE, about 7.5% PEG 40HCO, 1.0% preservative, about 1.0% xanthan gum and about 87.75% purified water.

[0288] The formulation is prepared by dispensing the desired amounts of rutin, trans-resveratrol, and diosmin and adding the three ingredients to a container of appropriate size. The desired amount of DEGEE is added to the container along with a magnetic stir bar and the mixture is stirred until the solids are dissolved. PEG 40HCO is a semisolid at room temperature with a melting point of approximately 50°C. It is heated to > approximately 50°C and added to the rutin / trans-resveratrol / diosmin / DEGEE mixture and the ingredients are mixed until uniform. The desired amount of purified water is added to the mixture while stirring to produce a clear nanoemulsion, followed by the addition of a preservative and xanthan gum. The resulting formulation can be used topically to treat varicose veins.

[0289] Although specific embodiments have been described above with reference to disclosed embodiments and examples, these embodiments are merely illustrative and do not limit the scope of the invention. Changes and modifications may be made according to ordinary skills in the art without departing from the broader aspects of the invention as defined in the claims.

[0290] All publications, patents and patent documents are incorporated herein by reference, as if individually incorporated by reference. Limitations inconsistent with the present disclosure should not be understood thereby. The present invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that changes and modifications may be made while remaining within the spirit and scope of the present invention.

Claims

1. A substantially oil-free or completely oil-free aqueous emulsion comprising: (i) from about 2.5 wt % to about 50 wt % of diethylene glycol monoethyl ether (DEGEE); (ii) about 5% to about 20% by weight of polyethylene glycol (PEG:H(OCH2CH2)) of castor oil n OH) derivatives, wherein n is 2 to about 1000; (iii) from about 60% to about 92% by weight water; and (iv) from about 0.01% to about 2% by weight of a poorly water-soluble compound dispersed in the emulsion; The aqueous emulsion is substantially free of oil phase or completely free of oil phase.

2. The aqueous emulsion of claim 1, wherein the compound comprises a natural product.

3. The aqueous emulsion according to claim 1, wherein the compound comprises: Fisetin; trans-resveratrol; milk thistle extract containing silymarin, quercetin and dihydroquercetin; curcumin; turmeric; (-)-epigallocatechin gallate (EGCG); rutin; salicylic acid; diosmin; imatinib; imatinib mesylate; and / or an extract of ophiopogon japonicus.

4. The aqueous emulsion according to claim 3, wherein the compound comprises: (i) fisetin, trans-resveratrol and / or milk thistle extract containing silymarin; (ii) EGCG and / or quercetin or dihydroquercetin; (iii) salicylic acid; or (iii) rutin, trans-resveratrol and / or diosmin.

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

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

7. The aqueous emulsion according to claim 1, wherein the compound comprises fisetin, trans-resveratrol and / or a milk thistle extract containing silymarin in the following ratios: (i) from about 0.075% to about 0.25% by weight of fisetin; (ii) from about 0.075% to about 0.15% by weight of trans-resveratrol; and / or (iii) about 0.125% to about 0.25% by weight of a milk thistle extract containing about 0.1% to about 0.2% by weight of silymarin.

8. The aqueous emulsion of claim 1, wherein the compound comprises from about 0.05% to about 0.1% of quercetin or dihydroquercetin.

9. The aqueous emulsion according to claim 1, wherein the compound comprises: (i) from about 0.03% to about 0.1% curcumin or turmeric; and / or (ii) about 1% to about 2% (-)-epigallocatechin gallate (EGCG).

10. The aqueous emulsion of claim 1, wherein the compound comprises from about 0.05% to about 0.1% of quercetin or dihydroquercetin.

11. The aqueous emulsion of claim 1 wherein the compound comprises from about 0.1% to about 1% salicylic acid.

12. The aqueous emulsion according to claim 1, wherein the compound comprises: (i) from about 0.25% to about 0.75% rutin; and / or (ii) from about 0.075% to about 0.15% by weight of trans-resveratrol.

13. The aqueous emulsion of claim 1, comprising nanoparticles having a d50 particle size and a number weighted average particle size both less than about 150 nm.

14. The aqueous emulsion of claim 1, wherein the aqueous formulation is formulated for topical, ocular, mucosal, intravenous, intramuscular or oral administration to a human or animal in need of the aqueous emulsion.

15. The aqueous emulsion of claim 14, wherein the aqueous emulsion is formulated for topical administration.

16. A method of promoting hair growth or treating skin disorders or varicose veins in a human or animal in need thereof, the method comprising topically applying to the skin of the human or animal a therapeutically effective amount of a substantially oil-free or completely oil-free aqueous emulsion for a therapeutically effective period of time, wherein the aqueous emulsion comprises: (i) from about 2.5 wt % to about 50 wt % of diethylene glycol monoethyl ether (DEGEE); (ii) about 5% to about 20% by weight of polyethylene glycol (PEG:H(OCH2CH2)) of castor oil n OH) derivatives, wherein n is 2 to about 1000; (iii) from about 60% to about 92% by weight water; and (iv) from about 0.01% to about 2% by weight of a poorly water-soluble compound dispersed in the emulsion; and The aqueous emulsion is substantially free of oil phase or completely free of oil phase.

17. The method of claim 16, wherein the compound comprises fisetin; trans-resveratrol; a milk thistle extract containing silymarin, quercetin, dihydroquercetin; curcumin; turmeric; (-)-epigallocatechin gallate (EGCG); rutin; salicylic acid; diosmin; imatinib; imatinib mesylate; and / or an extract of silymarin.

18. The emulsion of claim 17, wherein the compound comprises: (i) fisetin, trans-resveratrol and / or milk thistle extract containing silymarin; (ii) EGCG and / or quercetin or dihydroquercetin; (iii) salicylic acid; or (iii) rutin, trans-resveratrol and / or diosmin.

19. A method for preparing a substantially oil-free or completely oil-free aqueous emulsion comprising the steps of: (i) dissolving from about 0.05 wt % to about 2 wt % of a poorly water-soluble compound in from about 2.5 wt % to about 50 wt % of diethylene glycol monoethyl ether (DEGEE); (ii) diluting the mixture of step (i) with about 60% to about 92% by weight water; and (iii) adding about 5 wt % to about 20 wt % of polyethylene glycol (PEG:H(OCH2CH2)) of castor oil to the mixture of step (ii) n OH) derivatives, wherein n is 2 to about 1000; The aqueous emulsion is substantially free of oil phase or completely free of oil phase.

20. The method of claim 19, wherein the compound comprises fisetin; trans-resveratrol; a milk thistle extract containing silymarin, quercetin, dihydroquercetin; curcumin; turmeric; (-)-epigallocatechin gallate (EGCG); rutin; salicylic acid; diosmin; imatinib; imatinib mesylate; and / or an extract of silybum oleiferum.

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