Compositions and methods for improving the solubility of idebenone

Abstract

A method is disclosed for improving the solubility of a poorly soluble drug compound (PSD) both in vivo and in vitro, wherein the PSD is idebenone using a non-nutritive sugar or a surfactant, or a surfactant and a non-nutritive sugar in combination that is dissolved in a solvent. Non-nutritive sugars can include rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside.

Description

COMPOSITIONS AND METHODS FOR IMPROVINGTHE SOLUBILITY OF IDEBENONETECHNICAL FIELD

[0001] Disclosed are water-soluble complexes of a diterpene di-glycoside (“DTG”) or other non-nutritive sugar with a poorly soluble compound, such as idebenone, wherein the water-soluble complex significantly enhances the solubility of the poorly soluble drug both in vitro and in vivo. Also disclosed are water-soluble complexes of a surfactant and idebenone or a surfactant, a non-nutritive sugar, and idebenone. Methods for making such water-soluble complexes and pharmaceutical compositions comprising such complexes are also described.REFERENCE TO RELATED APPLICATIONS

[0002] This International Application claims benefit of and priority to U.S. ProvisionalApplications 63 / 585,154 and 63 / 613,443 filed respectively on September 25, 2023, and December 21, 2023, which are each herein incorporated by reference in their entirety for all purposes.BACKGROUND

[0003] The solubility of many compounds can play a critical role in their commercial utility, especially in the pharmaceutical industry. Compound solubility plays an important role in the compound’s effectiveness as a drug, especially in a number of essential pharmacokinetic (PK) properties. Poor drug solubility can lead directly to insufficient uptake, poor Cmax properties (e.g., maximum blood concentration), and the like. If a drug is not sufficiently soluble, it may not be fully absorbed into a subject’s blood circulation, which leads to insufficient Cmax to be efficacious (e.g., Ganesan et al., “Solubility: a speed-breaker on the drug discovery highway,” Bioequiv. Availab. 3(3): 56-8, 2017, Editorial).

[0004] Idebenone is an organic compound of the quinone family that was initially developed for possible treatment of cognitive defects but was not demonstrated to improve cognitive function. The European Medicines Agency (EMA) has approved it for the visual impairment in adolescent and adult patients with Leber’s hereditary optic neuropathy (LHON) Other indications have been explored, including Duchenne muscular dystrophy, and neuromuscular diseases.

[0005] Idebenone has structural similarity to ubiquinone, however, there are notable functional differences (Gueven et aS., 2015, “Border between natural product and drug:comparison of the related benzoquinones idebenone and coenzyme Q10,” Redox Biol. 4:289- 95. Epub 2015 Jan 14). An unfavorable property of idebenone is its poor water solubility (Montenegro et al., 2018, Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy. Nanomaterials (Basel). 8(2): 87). Idebenone also has been examined for clinical efficacy in photodamaged skin (McDaniel et al, 2005, “Clinical efficacy assessment in photodamaged skin of 0.5% and 1.0% idebenone,” J. Cosmet. Dermatol. 4(3): 167-73).

[0006] The ability to provide idebenone in a water-soluble topically deliverable form would present a significant improvement. Identifying a methodology that renders poorly soluble compounds, such as poorly soluble idebenone substantially more soluble in aqueous environments remains needed.SUMMARY

[0007] Provided herein are water-soluble complexes comprising one or more diterpene di-glycosides (DTG) or other non-nutritive sugar listed herein with a poorly soluble drug (PSD) wherein the drug is idebenone, and wherein the solubility of the water-soluble complex is significantly enhanced as compared to the PSD alone (e.g., not in the form of the water-soluble complex produced by the methods described herein). The water-soluble complexes described herein employ PSDs which are generally pharmaceutical compounds having at least one heteroatom capable of forming a hydrogen bond with the non-nutritive sugar. Not to be bound by a theory, it is believed that upon complexation (e.g., in the past was described as an aggregate but is described more appropriately as a complex given the hydrogen bonds and Van der Waals forces created between the surfactant and drug, the non-nutritive sugar and drug or the combination of the surfactant / non-nutritive sugar / drug) of the non-nutritive sugar with the PSD, a stable water-soluble complex occurs, presumably by non-covalent hydrogen bonding and optionally hydrophobic-hydrophobic interactions, such as van der Waal forces.

[0008] Also provided herein are water-soluble complexes comprising idebenone and a surfactant. A surfactant-idebenone water-soluble complex can also be formed by including a non-nutritive sugar. A water-soluble complex comprising a non-nutritive sugar, a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), and a drug compound, which water-soluble complex can comprise: a molar ratio of about 1 to 12 moles of the non-nutritive sugar and about 0.5 to 12.0 moles of the PSS or PXS, for each mole of said drug compound, wherein the sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; wherein the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, and Polysorbate 80 and the poloxamer surfactant is Poloxamer 188. The water-soluble complex formed can be stable in water at about pH 8.5 or at about pH 4.0 for at least 2 hours. The water-soluble complex formed should have the non-nutritive sugar present in a maximum amount of the sugar in a daily unit dose of said water-soluble complex at no more than about 280.0 mg.

[0009] In another embodiment, a water-soluble complex can be formed having a surfactant, and a poorly soluble drug (PSD or Drug) of either formula (II) or formula (III): [PSS]pDrug (Formula II) or [PXS]pDrug (Formula III), wherein the surfactant is a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), p can be a number from 1 to 5 and the drug compound (“Drug”) is an idebenone. The water-soluble complex is formed by admixing the surfactant and the Drug in a solvent until solubilized optionally in the presence of a pharmaceutically acceptable acid, drying the solvent from the Drug and the surfactant, dissolving the dried Drug and surfactant in water and optionally in a pharmaceutically acceptable acid, and wherein the Drug has an increased water solubility at 20 °C in the form of the water-soluble complex than the Drug when not in the water-soluble complex.Idebenone (2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-cyclohexa-2,5-diene- 1,4-dione; formula C19H30O5; CAS Number 58186-27-9) is an organic compound, specifically, a synthetic short-chain benzoquinone and therefore a member of the quinone family. It is soluble in chloroform, ethanol, and methanol. Trade names include Catena, Raxone, and Sovrima. Idebenone can be in the amount of a daily dosage of 150 mg or less per subject. An anti- wrinkle, anti-aging skin care composition may contain 1% idebenone or less weight per volume, 0.5% idebenone or less, or an anti-wrinkle / anti-aging sufficient amount. A composition comprising the water-soluble complex may further comprise a salt, such as NaCl or KC1.

[0010] As is well known, the sugar portion of a DTG (or other listed non-nutritive sugar) has a plurality of hydroxyl functionality capable of forming hydrogen bonds. In some cases, certain sugars may also contain a carboxyl group (e.g., sialic acid, glucuronic acid, etc.), an amino group (e.g., glucosamine), or a N-acetyl group (e.g., N-acetylglucosamine), each of which is capable of forming hydrogen bonds. The presence of such functionality allows a DTG (or other listed non-nutritive sugar) to participate in hydrogen bonding with a drug compound containing at least one heteroatom that is capable of forming hydrogen bonds with the DTG (or other listed non-nutritive sugar).

[0011] Without being limited by any theory, the contemplated mode of action utilizes the plurality of hydroxyl groups on the sugar units in the DTG (or other listed non-nutritive sugar) to create a multiplicity of points for aggregation and / or complexation between the hydroxyl functionality of the sugar units on the DTGs (or other listed non-nutritive sugars) and heteroatoms of the drug that individually do not create sufficient adhesion to maintain a stable complex. Through aggregation, a cumulative amount of adhesion is achieved which provides for a stable water-soluble complex. In addition, the diterpene component of the DTG (or other listed non-nutritive sugar), it is believed, uses hydrophobic -hydrophobic interactions with the drug that provides for regions of hydrophobic and hydrophilic binding elements. It is further contemplated that these hydrophobic and hydrophilic regions will partition into the hydrophobic interactions being maintained in the interior of the water-soluble complex while the exterior of the complex displays hydrophilic interactions rendering the water-soluble complex soluble in aqueous solutions.

[0012] Disclosed are water-soluble complexes of a diterpene di-glycoside (“DTG”) (or other listed non-nutritive sugar) with idebenone wherein said water-soluble complexes are capable of topical delivery to patients in need thereof.

[0013] In one embodiment, the water-soluble complexes described herein can be represented by Formula I as follows:[DTG]pDrug (I) where DTG (which can also be another non-nutritive sugar when DTG is used in the formula) and drug (e.g., idebenone) are as defined herein and p is a number from 1.5 to 12 moles.

[0014] As defined below, DTGs are diterpene glycosides commercially available as a natural sweetener. Such DTGs include stevioside and rubusoside, as well as other related compounds listed herein.

[0015] Disclosed herein and contemplated is a water-soluble complex comprising a sugar and a poorly water-soluble drug, e.g., idebenone, which water-soluble complex comprises: a molar ratio of up to about 12 moles of the sugar for each mole of said poorly water-soluble drug, wherein the sugar is one or more of rubusoside, dulcoside B, dodecyl-P-D- maltoside, stevioside, or rebaudioside A, provided that said water-soluble complex has at least a two, three, four or five (5) fold increase in the water solubility of said poorly soluble drug at 20° C as compared to the water solubility of said drug that is not in said water-soluble complex form; and further provided that a maximum amount of the sugar in a daily unit dose of saidwater-soluble complex is no more than about 10 mg / kg subject weight. In another embodiment, the sugar used to make the water-soluble complex can be rubusoside or stevioside.

[0016] In certain embodiments, the water-soluble complex is comprised of a sugar selected from the group of rubusoside, rebaudioside A, dodecyl-P-D-maltoside, dulcoside B, or stevioside or any combination thereof.

[0017] In other embodiments, the water-soluble sugar-drug complex is comprised of a non-nutritive sugar selected from the group of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A. In other embodiments, the water- soluble sugar-drug complex is comprised of a non-nutritive sugar selected from the group consisting of rubusoside, rebaudioside A, dodecyl-P-D-maltoside, dulcoside B, stevioside, or any combination thereof. In still another embodiment, the complex may be formed using rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A, or combinations thereof. In another embodiment, the water-soluble sugar-drug complex uses either rubusoside, stevioside, or a combination thereof.

[0018] In a further embodiment, the amount of the DTG sugar (or other non-nutritive sugar) in the daily unit dose administered to a subject amounts to no more than about 5 mg / kg of subject weight. In another embodiment, the water-soluble complex comprises an amount of the DTG sugar (or other non-nutritive sugar) in the daily unit dose of no more than about 280 mg.

[0019] In an embodiment, the water-soluble complex comprises a molar ratio (moles of poorly-soluble drug (PSD) to moles of sugar; PSD:DTG sugar or non-nutritive sugar) of about 1:1 to about 1:12, about 1:1 to about 1:10, or about 1:1 to about 1:5 moles. In an embodiment, the water-soluble complex comprises about 3.0 moles of the DTG sugar (or other non-nutritive sugar) for each mole of said poorly water-soluble drug, i.e., about 1:3 molar ratio.

[0020] In another embodiment, the water-soluble complex comprises a molar ratio of about 2 to about 5 moles of the DTG sugar (or other non-nutritive sugar) for each mole of said poorly water-soluble drug, i.e., molar ratio PSD:sugar of about 1:2 to about 1:5.

[0021] In another embodiment, the water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of the DTG sugar (or other non-nutritive sugar) for each mole of said poorly water-soluble drug, i.e., molar ratio PSD:sugar of about 1:2 to about 1:4.5.

[0022] Another embodiment contemplates the water-soluble complex being stable when dissolved in water at pH 8.5 for at least about 2 hours.

[0023] In a further embodiment, the water-soluble complex is stable when dissolved in water at about pH 4 for at least about 2 hours.

[0024] A further embodiment contemplates that the dried form of the water-soluble complex is stable at 30 °C for at least 90 days.

[0025] A further embodiment contemplates that the water-soluble complex is stable at room temperature for about 24 hours. Another embodiment contemplates that water-soluble complex does not require refrigeration for at least 24 hours.

[0026] Another embodiment contemplates the water-soluble complex in the form of a cream, a topical cream, an ointment, a gel, a soft gel, a syrup, a solution, an elixir, a liquid, an emulsion, a transdermal patch, or any other formulation suitable for topical application. Another embodiment contemplates the water-soluble complex in the form of a cosmetic or dermatological composition. Another embodiment contemplates a cosmetic or dermatological composition, wherein the water-soluble complex is present in the cosmetic or dermatological composition at from about 0.01% to about 5% w / v percent (weight idebenone / volume composition) or from about 0.01% to about 5% w / v percent (weight water-soluble complex of idebenone / volume composition). A dermatological composition may further comprise a salt such as NaCl or KC1.

[0027] Alternatively, the water-soluble complex can be in the form of a powder, a tablet, an orally disintegrating tablet, a capsule, a thin film, a lozenge, a chewable pill or gummy, or an effervescent powder or tablet. Alternatively, the water-soluble complex can be a formulation prepared for parenteral administration and can be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intravenously, metered nasal spray, or eye drop. A further embodiment contemplates the water-soluble complex formulated as a thin film, an effervescent powder or tablet, a chewing gum, a gummy, a lollipop, a sublingual drop, or a tincture.

[0028] Another embodiment contemplates a water-soluble complex comprising a sugar and a poorly water-soluble drug, which water-soluble complex comprises: a molar ratio of about 3 moles of the non-nutritive sugar for each mole of said poorly water-soluble drug, wherein the sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; wherein said water-soluble complex is stable in water at pH 8.5 and at pH 4.0 for at least 2 hours each; provided that said water-soluble complex has at least about a two, three, four or five (5) fold increase in the water solubility of said poorly soluble drug at 20° C as compared to the water solubility of said poorly water-soluble drug not in the water-soluble complex; and further or optionally provided that a maximum amount of the non-nutritive sugar in a daily unit dose of said water-soluble complex is no more than about 280 mg.

[0029] Another aspect contemplates a method of making a water-soluble complex comprising a non-nutritive sugar (or combination of non-nutritive sugars) and a poorly water- soluble drug (PSD), the method comprising the steps of admixing, in at least 85% ethanol (or at least 90% or 95%), the sugar with the PSD in a molar ratio of from about 1.0 to about 5.0 moles of the non-nutritive sugar for each mole of said poorly water-soluble idebenone compound until solubilized thereby forming the water-soluble complex, wherein the formation, existence, or presence of the water-soluble complex can be determined by nuclear magnetic resonance (NMR) spectroscopy, and wherein the non-nutritive sugar is one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-P-D-maltoside (DDM), or stevioside or another non-nutritive sugar listed herein; and wherein the admixing step is optionally performed with a pharmaceutically acceptable acid; and optionally drying the water-soluble complex. A further method contemplates that the sugar used in the method is rubusoside or stevioside. The poorly water-soluble (i.e., PSD) used in the method of making the water- soluble complex can be idebenone or a pharmaceutically acceptable salt thereof.

[0030] The dissolving method for the first solvent step or the water step (second step) can optionally include one or more acids or bases to further improve the solubility and / or stability of the drug-sugar complex formed by the method. Preferably, the acid or base is a pharmaceutically acceptable acid or base when used with a drug. The acid or base can be added until solubility is achieved for the drug compound and the sugar.

[0031] For the first step, the drug compound must be one that can be solubilized fully or partially in either 95% ethanol, absolute ethanol, an aqueous ethanol solution of 50% ethanol or greater (e.g., 50%, 55%, 60%, 70%, 80%, 85% 90%, 91%, 92%, 93%, 94%, and 95% spectrophotometric grade ethanol as well absolute ethanol) in the presence of a sugar. Drugs and chemicals contemplated include those drugs that are insoluble, have limited solubility, and are soluble in water. The compound or drug compound can be any free form of a compound or its salt, hydrate, or polymorph, or a salt of the indicated free form of the drug compound.The drug compound and sugar are solubilized in at least about 85% ethanol, and optionally in the presence of an acid or a base. In another embodiment, methanol can be added to the ethanol, drug compound, sugar, and optionally acid / base to further solubilize and form the water- soluble complex. Optionally, the water-soluble complex remains soluble without the formation of a precipitate for at least 24 hours after formation of the water-soluble complex. Alternatively, the solvent may be a co- solvent such as a binary or ternary (or higher) mixture of solvents. For example, the co-solvent can be about 50% ethanol with a buffer or water in the remainder, or, alternatively, a different or further solvent can be used in combination with water or an aqueous buffered solution. Frequently, a ratio of as little as about 1:0.00005 of ethanol to methanol (e.g., 95% or greater methanol) can improve solubility over ethanol alone. Therefore, a range of 1:1 ethanol to methanol to 1:0.00001 (and all 0.00001 values within that range) is contemplated. In some embodiments, methanol can be used in place of ethanol such that the ratios of methanol to ethanol are reversed to those cited above (e.g., 1:1 methanol to ethanol to 1:0.00001 methanol to ethanol with all values therebetween included). It can also be a combination of ethanol, methanol, and isopropanol.

[0032] Other pharmaceutically acceptable solvents that can be used alone or in combination to form the water-soluble complex include acetone, acetonitrile, anisole (methoxybenzene), benzene, 1 -butanol, 2-butanol, butylacetate, tert-butylmethylether, carbon tetrachloride (tetrachloromethane), cumene, cyclohexane, 1,2-dichloroethane, 1,1- dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), 1,4-dioxane, ethanol, 2- ethoxyethanol, ethylacetate, 2-ethoxyethanol, ethylacetate, ethyleneglycol, ethylether, ethylformate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, 2-methoxyethanol, methyl acetate, 3-methyl-l -butanol (isoamylalcohol), methylbutyl ketone, methylcyclohexane, methylethyl ketone, methylisobutyl ketone, 2- methyl-1 -propanol, N-methylpyrrolidone, nitromethane, pentane, 1 -pentanol, 2-propanol, propyl acetate, pyridine, sulfolane, tetrahydro furan, tetralin, toluene, 1,11 -trichloroethane, 1,1,2-thichloroethene, triethylamine, and xylene. In another embodiment, the solvent, or solvent combination, may be water, ethanol, DSMO, DMF, methanol, acetone, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, or toluene. Organic solvents contemplated alone or in combination for step 1 include hexane, p-xylene, toluene, ether, methyl t-butyl ether (MTBE), diethylamine, dioxane, chlorobenzene, tetrahydro furan, orthodichlorobenzene (ODCB), ethyl acetate, dimethoxyethane, pyridine, methylene chloride,HMPT, 1,2-di-chloroethane, DMPU, acetone, dimethylformamide, t-butyl alcohol, sulfolane, dimethylsulfoxide, acetonitrile, nitromethane, 2-propanol, benzyl alcohol, ethanol, methanol, ethylene glycol, trifluoroethanol, hexafluoroisopropanol, and water. Water is preferably deionized water or distilled water or deionized and distilled water. The non-nutritive sugar and the PSD should dissolve in the solvent or solvent combination for the method. Preferable solvents include ethanol, methanol, chloroform, hexane, and aqueous forms of the same. FDA- approved solvents are provided in the Q3C - Tables and List Guidance for Industry from June 2017. An FDA approved solvent can be one or more of acetonitrile, chlorobenzene, cyclohexane, cumene, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N- dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, methylisobutylketone, N-methyl pyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene within the FDA limits of what can be present. Another list of FDA solvents for use in step 1 includes one or more of acetone, anisole, 1 -butanol, 2-butanol, butylacetate, tert-butylmethylether, dimethylsulfoxide, ethanol, ethylacetate, ethyl ether, ethyl formate, heptane, isobutylacetate, isopropylacetate, methylacetate, 3-methyl-l -butanol, methylethylketone, 2-methyl-l -propanol, pentane, 1- pentanol, 1 -propanol, 2-propanol, propyl acetate, and triethylamine.

[0033] The methods of making the water-soluble complex may in some instances further include a surfactant in either the solvent step (step 1) or the water step (step 2) of the methods described herein. The surfactant can also be used in combination with an acid or base in the solution. The surfactant can be a polysorbate surfactant (PSS) and / or a poloxamer surfactant (“PXS”). PXS are poloxamer surfactants, which are a class of synthetic nonionic amphiphilic triblock linear copolymers composed of a central hydrophobic chain of non-polar blocks of poly(propylene oxide) (PPO) blocks flanked by two hydrophilic chains of polar blocks of poly(ethylene oxide) (PEO). Poloxamer surfactants are available in different molecular weights and PPO / PEO ratios. PXS surfactants are commercially available as, for instance, Kolliphor® P (BASF, Florham Park, NJ), Pluronic® (BASF, Florham Park, NJ), Lutrol® (BASF SE, Ludwigshafen, Germany) and Synperonic™ PE (CRODA International PLC, East Yorkshire, United Kingdom). PXS surfactants are available in liquid, flake, and paste physical forms. In an embodiment, the PXS is flake solid. Polysorbate surfactants(“PSS”) are derived from ethoxylated sorbitan esterified with fatty acids and are commercially available as, for instance, Tween® (Croda International LLC, Wilmington DE)and Kolliphor® PS (BASF SE, Ludwigshafen, Germany). Polysorbate surfactants include Polysorbate 20 (e.g., Tween® 20), Polysorbate 40 (e.g., Tween® 40), Polysorbate 60 (e.g., Tween® 60), Polysorbate 65 (e.g., Tween® 65), and Polysorbate 80 (e.g., Tween® 80). The number following “polysorbate” relates to the major fatty acid associated with the molecule. For instance, “20” indicates monolaurate, and “80” indicates monooleate. Tween® 80 may also be referred to herein as T80 and similarly for the other types of Tween®.

[0034] The method further can comprise drying the water-soluble complex to form a solid. The dried solid can be re-dissolved into a suitable liquid.

[0035] In some embodiments, the method of preparing the water-soluble complex may further require the presence of a pharmaceutically acceptable acid to be added in the admixing step when dissolved in the solvent of step 1 and / or in the water dissolving step after complex formation in step 2 in the presence of a sufficient amount of a pharmaceutically acceptable acid to solubilize and render the reaction mixture homogeneous and clear. The pharmaceutically acceptable acid to be used in the method can be acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

[0036] The method can use the surfactant with a solvent alone or also in the presence of an acid or a buffer. The solvent used in the method can be a pure solvent, such as absolute ethanol, or a mixture of solvents such as ethanol, water, and methanol as suggested herein. The sugar, drug compound, and solvent can have the surfactant with them in a vessel and the pH can then be adjusted until a homogeneous solution is formed. Preferably the homogeneous solution remains stable for at least 30 minutes, more preferably at least 2 hours, more preferably at least about 24 hours.

[0037] The method of making the water-soluble complex can admix a molar ratio of about 1 to about 12 moles of the sugar for each mole of said poorly water-soluble drug (PSD). The sugar can be any of the DTGs discussed herein, for example, stevioside and rubusoside. Alternatively, the water-soluble complex made by the method can have a molar ratio of about 2 to about 10 moles of the sugar for each mole of said poorly water-soluble drug (i.e., about 1 :2 to about 1 : 10 molar ratio drug:sugar), or from about 3 to about 5 moles of the sugar to each mole of PSD (i.e., about 1:3 to about 1:5 molar ratio drug:sugar). In another embodiment, theformed water-soluble complex from the method can comprise a molar ratio of about 3 moles of the sugar for each mole of said poorly water-soluble drug (about 1:3 molar ratio PSD:sugar), as well as any 0.1 amount between 1:1.0 and 1:12.0.

[0038] These and other embodiments will be apparent to those of skill in the art upon reading the specification.DETAILED DESCRIPTION

[0039] Creating new means of solubilizing compounds can assist compounding pharmacies and drug manufacturers in formulating patient-specific amounts of an active compound as well as formulating the active compound into palatable formulations (e.g., for patients who prefer a sweeter taste, such as for pediatric patients). The proposed sugar-drug combinations are believed, without limitation to theory, to be created by hydrogen bonding or by host-guest chemistry (e.g., to form an inclusion compound or inclusion complex), wherein two compounds are in a complex and / or complex in which one chemical compound forms a cavity into which a "guest" compound can be accommodated. The interaction between the host and guest in an inclusion complex involves purely van der Waals bonding. In this sugar- compound form, the complex and / or complex formed from the sugar compound increases the compound’s solubility in water over the compound alone (not in a complex). The complex also imparts a sweeter taste, instead of a bitter or acrid taste imparted by many salts; however, the addition of the sugar to form the complex is not as a sweetener, but rather to form a complex with idebenone to enhance water-solubility when in the form of a complex. The sweeter taste will be of benefit when administering pharmaceuticals to young children as well as to geriatric patients.

[0040] While the complexed non-nutritive sugar and drug may be more palatable as a complex, it must be understood that the formation of the complex is not merely to mask a drug’s taste. Improving the palatability of a drug is a side benefit. The formation of the water- soluble sugar-drug complex by the methods described herein results in improved characteristics of the drug in the form of a complex such as improved water solubility. Additionally, improved characteristics can include improved pharmacokinetic attributes, improved stability at a pH and / or storage, and high temperatures or other conditions. Pharmacokinetic attributes include absorption into a system, its distribution in the system, the system’s metabolism of the complex, and its elimination. Moreover, given the data and description herein, it should be understood that the water-soluble drug- sugar complex is formed by the methods described herein but isnot to be considered as a mixture. The method of solubilizing a listed non-nutritive sugar with the PSD in a listed solvent or solvent combination can optionally be in the presence of an acid / base / polysorbate surfactant, followed by drying using the methods described herein. The dried complex is then dissolved in water, and optionally filtering and / or drying the complex. The final complex yields a new more water-soluble drug in the form of a complex. The water- soluble sugar-drug complex can then be further mixed with other pharmaceutical excipients, stabilizers, fillers, flavorings, sweeteners, and the like as mentioned here. After adding one or more of these other components, only then would the composition be in the form of a mixture. The complex formed by the methods disclosed involves host-guest chemistry that is not contemplated when forming such mixtures. The solubility of the complex is not dependent on the addition of other pharmaceutical excipients, stabilizers, fillers, flavorings, sweeteners, and the like. Contemplated compositions may further comprise a salt such as NaCl or KC1.

[0041] Another benefit achieved by the method and products produced by the method is a decreased amount of an active drug agent because with greater solubility there will be greater bioavailability. The method provides a cost-benefit of having to utilize fewer resources for less of an active compound but still achieving the desired patient outcome.

[0042] Complexation of the drug with the DTG or other non-nutritive sugar can be construed as a donor (sugar) receptor (drug) interaction, such as host-guest chemistry between the drug and the one or more sugars. In effect, the complexation intertwines the poorly soluble drug with the soluble non-nutritive sugar, which essentially allows the drug to capture the water solubility of the non-nutritive sugar. See, for example, “Absorption and distribution of steviol glycosides in animal and human models.” Stevia Technology. Retrieved July 31, 2023, from: https: / / www.steviashantanu.com / single-post / 2015 / l l / 18 / absorption-and-distribution-of- steviol-glycosides-in-animal-and-human-models. Without being limited to any theory, enzymatic cleavage of the glucose groups results in disaggregation (e.g., decomplexation) of the sugar-drug complex, which releases the poorly soluble drug. This process is sufficiently slow that substantial portions of an amount of the drug released at any given time can be absorbed.Definitions

[0043] The following definitions provide guidance on term interpretation unless otherwise indicated by the context in which the term appears elsewhere in the specification.

[0044] As used herein, the term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0045] As used herein, the term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations that may vary by (+) or (-) 15%, 10%, 5%, 1%, or any subrange and / or value therebetween. The term “about” when used concerning a dose amount means that the dose may vary by + / - 10%. The term “about”, when modifying the quantity (e.g., kg, L, or equivalents) of a substance or composition, the value of a physical property, or the value of a parameter characterizing a process step (e.g., the temperature at which a process step is conducted), or the like refers to variation in the numerical quantity that can occur, for example, through typical measuring, handling and sampling procedures involved in the preparation, characterization and / or use of the substance or composition; through an inadvertent error in these procedures; through differences in the manufacture, source, or purity of the ingredients employed to make or use the compositions or carry out the procedures; and the like. In certain embodiments, “about” can mean a variation of ±0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 of the appropriate unit. In certain embodiments, “about” can mean a variation of ±1%, 2%, 3%, 4%, 5%, 10%, or 20%.

[0046] As used herein, the term “comprising” or “comprises” is intended to mean that the compositions or methods include the recited elements, but do not exclude others.

[0047] As used herein, the term “consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose of improving the solubility of idebenone. Thus, a composition consisting essentially of the elements as defined herein, or a method consisting essentially of the steps as defined herein, would not exclude other materials that do not materially affect the basic and novel characteristic(s) of the claimed subject matter.

[0048] As used herein, the term “consisting of’ shall mean excluding more than trace elements of other ingredients or substantial method steps. Embodiments defined by each of these transition terms are within the scope of this disclosure.

[0049] The “molar ratio” of a “non-nutritive sugar to a drug compound” in a formulation may range from about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1 to about 20:1 and any 0.1 value between. Alternatively, the sugar-to-drugcompound ratio can be about 1.00: 1.00 to about 5.00: 1.00, and any 0.01 value within that range.In one embodiment, an about 2.0 to about 1.0 molar ratio of sugar to PSD is used.

[0050] The use of the terms “sugar” and “non-nutritive sugar” means that the sugar is a non-nutritive sweetener. A non-nutritive sugar has a sweetness of at least 50 times that of glucose with essentially no calories. One type of non-nutritive sugar is a diterpene glycoside, “DTG,” as used herein. Exemplary DTGs can be rubusoside, dulcoside B (also known as rebaudioside C), stevia, rebaudioside A (also known as stevioside A3), stevioside (a type of diterpene glycoside and has a chemical formula of CasHeoOis), n-octyl glucose, n-dodecyl-P- D-maltoside (also known as dodecyl maltoside or lauryl maltoside), stevia (has a chemical formula of C44H70O23), and a steviol glycoside such as that derived from Stevia rebaudiana. It can also be any of the other sugars discussed herein. While other stevia-like sugars are known, only those that are FDA GRAS-approved are contemplated for use in the water- soluble sugar-drug complex for administration to a human subject. Preferably, the sugar is one or more of rubusoside, stevia, dulcoside B, stevioside, n-dodecyl-P-D-maltoside, or rebaudioside A which can be used in any combination or permutation. Also contemplated is any permutation of these listed 6 sugars (2 of the sugars, 3 of the sugars, etc.). The price of the sugar can be a factor in whether a sugar is commercially a good sugar for solubilizing a poorly soluble or soluble drug compound. Exemplary sugars for making the “water-soluble sugar-drug complex” are rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, rebaudioside A, rebaudioside B, rebaudioside D, stevioside, stevia n-octyl glucose, or n-dodecyl-P-D-maltoside.

[0051] Not to be bound by a theory, it is believed that when a contemplated non- nutritive sugar as discussed herein complexes with the drug compound, a stable complex occurs, presumably by non-covalent hydrogen bonding and optionally hydrophobichydrophobic interactions, such as van der Waal forces. A “sugar” or “non-nutritive sugar” as used herein can be dulcoside A, sucrose, D-fructose, sucralose, a rebaudioside B, rebaudioside D, stevia, n-octyl glucose, Advantame®, neotame®, thaumatin, saccharin, Lou Han Guo, aspartame, acesulfame potassium (Ace-K), allulose, rubusoside, dulcoside B (also known as rebaudioside C), rebaudioside A (also known as stevioside A3), a stevioside (also known as diterpene diglycoside or herein as DDG), n-octyl glucose, and a steviol glycoside such as that derived from Stevia rebaudiana.

[0052] ADVANTAME® - is an aspartame analog; N-[N-[3-(3-hydroxy-4- methoxyphenyl) propyl] -a-aspartyl]-L-phenylalanine-l -methyl ester (Otabe et al.,“Advantame® - An Overview of Toxicity Data,” Food and Chemical Toxicity 49(S1): S2- S7, 2011. Advantame® has a low glycemic index (GI) and zero calories but can cause a spike in insulin.

[0053] NEOTAME® - tradename is Newtame® and is a derivative of aspartame that is classified as an aspartyl-derived dipeptide. Neotame® has a low glycemic index (GI) and zero calories but can cause a spike in insulin.

[0054] Thaumatin - is also known as TALIN®, Soma sweet. It is a mixture of the sweet proteins thaumatin I and thaumatin II derived from Thaumatococcus danielli.

[0055] Saccharin - is also known as saccharine or benzosulfimide and in such salt forms as saccharin sodium and saccharin calcium. It is sold under the brand names Sweet and Low®, Sweet Twin®, Sweet’N Low® and Necta Sweet®. Saccharin has a low glycemic index (GI) and zero calories but can cause a spike in insulin.

[0056] Sucralose - sold under the name Splenda and is an organochlorine sweetener having the chemical name of l,6-dichloro-l,6-dideoxy-P-D-fructofuranosyl-4-chloro-4- deoxy-a-D-galactopyranoside (Schiffman et al., “Sucralose, A Synthetic Organochlorine Sweetener: Overview of Biological Issues,” J. Toxicol Environ. Health B. Crit. Rev. 16(7): 399-451, 2013). Sucralose has a low glycemic index (GI) and zero calories but can cause a spike in insulin.

[0057] Lou Han Guo - also goes by the name of Siraitia grosvenorri, swingle fruit, monk fruit, and luohan guo from which sweeteners can be derived that have no calories. The FDA has called this Swingle Fruit Extract (SGFE). The compounds that give the sweetness are mogrosides, which have a mogrol backbone and glucose units (glycosides) attached to them. They may be sold under the brands Monk Fruit in the Raw®, Lakanto®, PureLo®, SPLENDA® Monk Fruit Sweetener, SweetLeaf®, and Whole Earth®. SGFE does not appear to raise blood sugar levels.

[0058] Aspartame - is sold under the names Nutrasweet, Equal, and Sugar Twin and does contain calories. The chemical name is L-aspartyl-L-phenylalanine methyl ester. It is a dipeptide composed of phenylalanine and aspartic acid. Aspartame has a low glycemic index (GI) and zero calories but can cause a spike in insulin.

[0059] Acesulfame potassium - is also known as Ace-K and is sold under the brand names Sweet One® and Sunett®. Ace-K has a low glycemic index (GI) and zero calories but can cause a spike in insulin.

[0060] Allulose - is a sugar that naturally occurs in figs and raisins. It is also known as D-psicose or D-allulose and has few calories. It does not impact insulin or blood sugar levels. Tani et al., “Allulose for the attenuation of postprandial blood glucose levels in healthy humans: A systematic review and meta-analysis,” PLoS One 18(4): e0281150, 2023.

[0061] The sweetness of a non-nutritive sugar is compared to table sugar (sucrose) and is summarized in the following table obtained from the US FDA:

[0062] By a “compound”, “drug compound”, and “poorly soluble drug” is idebenone or a salt thereof, wherein the idebenone or a salt thereof, is poorly soluble or insoluble in water (e.g., a poorly soluble drug, PSD). While not being bound by theory, the drug compound preferably has available hydrogen bonding sites to form such bonds with a sugar and / or for the compound and the sugar to form an inclusion complex. For the compounds and methods described herein, the PSD is a poorly soluble idebenone, free form or polymorph of idebenone, or a pharmaceutically acceptable salt thereof. A poorly water soluble drug compound is a compound that can dissolve at no more than about 10 mg per milliliter of water and generally less than 1 mg per milliliter.

[0063] A “stable” sugar-compound is a water-soluble complex (i.e., [DTGpDrug) prepared by the methods described herein that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of timesufficient to allow the use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0064] The methods described herein comprise dissolving a drug compound in ethanol (or another listed solvent or solvent combination) in the presence of an indicated sugar, followed by drying or evaporating (e.g., freeze-drying or lyophilizing or other means of evaporating the ethanol or other solvent from the mixture) the liquid from the composition. Evaporation can use various steps including pre-freezing of the complex followed by primary and secondary drying steps. If lyophilization is employed, conventional lyophilization aids can be used in combination with the complex in solution. The dried complex is then solubilized in water and can be evaporated again if necessary. The complex dried after being solubilized in water can also be filtered. The complex dried after being solubilized in water can also be formulated into a pill or in any of the other forms described herein. In another embodiment, the solvent, or solvent combination, may be water, ethanol, DSMO, DMF, methanol, acetone, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, or toluene. Water is preferably deionized water or distilled water or deionized and distilled water. A solvent can also be can be one or more of acetonitrile, chlorobenzene, cyclohexane, cumene, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N- dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, methylisobutylketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, and xylene within the FDA limits of what can be present. Another list of FDA approved solvents for use in step 1 includes one or more of acetone, anisole, 1 -butanol, 2-butanol, butylacetate, tert-butylmethylether, dimethylsulfoxide, ethanol, ethylacetate, ethyl ether, ethyl formate, heptane, isobutylacetate, isopropylacetate, methylacetate, 3-methyl-l -butanol, methylethylketone, 2-methyl-l- propanol, pentane, 1 -pentanol, 1 -propanol, 2-propanol, propyl acetate, and triethylamine.

[0065] The term “cosmetic use” means a non-therapeutic use, i.e., a use that does not require a therapeutic treatment requiring approval by the EMA or U.S. Food and Drug Administration (FDA) or their equivalent agency in another country to treat a patient. That is, a “cosmetic use” is the administration of a composition intended for healthy skin and / or mucous membranes, i.e. skin not presenting a dermatological pathology. The term “dermatological use” means a use for skin presenting, i.e., a dermatological pathology. Exemplary skin includes but is not limited to all or part of the face, and / or the body chosen from the legs, the hands, thethighs, the stomach, the neckline, the neck, the arms, the torso, the back, the face, and the area around the eyes.

[0066] The water-soluble drug complex (e.g., hydrogen-bonded and / or inclusion complexed sugar-compound) can be formulated into a cosmetic or dermatologic composition, such as a serum, lotion, cream, stick, wash, gel, emulsion, mask composition, and / or ointment. Such compositions can comprise one or more conventional cosmetic adjuvants or additives, for instance, fragrances, chelating agents (for example, disodium EDTA), preserving agents (for example, chlorphenesin and phenoxy ethanol), and bactericides, surfactants, thickeners, fillers (for example, stearalkonium hectorite), pH regulators (for example citric acid or sodium hydroxide), and mixtures thereof. Components in such formulations may include one or more of glycerin, isohexadecane, a vitamin (e.g., vitamin E, niacinamide, vitamin B3, vitamin C, peptides), distarch phosphate, isopropyl isostearate, dimethicone, panthenol, palmitoyl pentapeptide-2, sodium hyaluronate, caprylic or capric triglyceride, an alpha hydroxy acids (e.g., glycolic acid or lactic acid for dead skin removal and new skin promotion), ethylhexylglycerin, hyaluronic acid, collagen, a retinol (e.g., retinoic acid, bakuchiol), a ceramide, a starch, ferulic acid, hydroxyacetophenone, biotin, an oil (e.g., jojoba oil), an enzyme (e.g., coenzyme Q10), dimethiconol, cetearyl glusoside, an anti-oxidant, ceteraryl alcohol, stearic acid, palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, disodium EDTA, sodium acrylates copolymer, kojic acid, hydroquinone, PEG- 100 stearate, green tea or tea derived component, calcium, a component of aloe vera, titanium dioxide, mica, phenoxyethanol, and a fragrance. A composition may further contain one or more active sunblocking agents such as avobenzone, homosalate, octisalate, ocrocrylene, or zinc.

[0067] Exemplary hydrophilic thickeners for use in a cosmetic formulation can be selected from anionic, cationic, amphoteric or nonionic chitin or chitosan polymers; cellulose polymers, in particular (C1-C3) hydroxyalkylcelluloses, selected from hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose and quatemized derivatives of cellulose; vinyl polymers, for instance polyvinylpyrrolidones, copolymers of methyl vinyl ether and of malic anhydride, the copolymer of vinyl acetate and of crotonic acid, copolymers of vinylpyrrolidone and of vinyl acetate; copolymers of vinylpyrrolidone and of caprolactam; polyvinyl alcohol, optionally modified polymers of natural origin, such as galactomannans and derivatives thereof, for instance carrageen gum, konjac gum, gellan gum, locust bean gum, fenugreek gum, karaya gum, gum tragacanth, gum arabic, acacia gum, guar gum andderivatives thereof (carboxymethyl guar, hydroxypropyl guar, hydroxypropyl guar modified with sodium methylcarboxylate groups (Jaguar XC97-1, Rhodia)), xanthan gum and derivatives thereof; alginates and carrageenans, for example, carrageenans of the p, K, V, r, A or 9 types, and mixtures thereof in all proportions, preferably K type; mucopolysaccharides such as hyaluronic acid; and mixtures thereof. Exemplary emulsions are disclosed, for instance, in U.S. Patent Publication 20230201088. Exemplary mask compositions are disclosed, for instance, in WO 2022 / 110183.

[0068] A cosmetic formulation would be for use in applying to the skin of a subject such as to the body, the scalp, neck, and face. It can be combined with one or more other compounds in the preparation for use in treating skin wrinkles, skin smoothing, and to inhibit or slow the progress of skin aging. Additional compounds can include anti-acne agents, such as salicylic acid or benzoyl peroxide, octopirox, dextrorotary and levorotary sulfur-containing amino acids, their salts, and their N-acetyl derivatives such as N-acetyl cysteine, or agents seeking to prevent aging of the skin and / or to improve its state, for example the above- mentioned a- and -hydroxy acids, retinoids such as retinoic acid, retinol, and its esters, such as, for example, retinyl propionate, and retinyl acetate, or retinyl palmitate, niacinamide, allantoin, extracts of aloe, azelaic acid, bisabolol, phytic acid, collagen, or agents stimulating the formation of collagen, vitamins such as vitamin C or derivatives thereof, such as ascorbyl glucoside, vitamin E or derivatives thereof, vitamin A or derivatives thereof, vitamin F or derivatives thereof, dextrorotary and levorotary sulfur-containing amino acids and derivatives thereof as mentioned above, elastin, N-acetyl D-glucosamine, luteol in, or antioxidants such as green tea or active fractions thereof, glycerin, laponite, caffeine, essential aromatic oils, coloring agents, free-radical scavengers, moisturizers, depigmenting agents, agents for improving the color of the skin such as artificial-tanning agents of the dihydroxyacetone or tyrosin ester type, liporegulators, softeners, anti-wrinkle agents, keratolytic agents, fresheners, deodorants, anesthetics, nourishing agents, and mixtures thereof. It is also possible to use bleaching agents such as kojic acid, ascorbyl phosphates, ascorbyl glucosides, ascorbic acid, and mixtures thereof.

[0069] The water-soluble complex formed by the method can alternatively be formulated into a solid form for oral, sublingual, and / or buccal administration, such as a pill, capsule, a caplet, a chewable (e.g., a gummy), tablet, a lozenge, and / or a soft gel. The water- soluble drug complex (hydrogen-bonded and / or inclusion complexed sugar-drug compound) can also be formulated as an inhalable powder. In another aspect, the water-soluble complexcan be formulated into an injectable liquid for injection into a subject subcutaneously (SC), intravenously (IV), intraperitoneal (IP), and intramuscularly (IM). Such formulations can be for cosmetic use or therapeutic use. Alternatively, the lyophilized water-soluble complex can be formulated into a liquid formulation for administration such as for use in a metered nasal spray, inhaled mist, eye drop, or nebulized by a patient. In the case of non-human subjects, a lyophilized water-soluble complex can be administered to a non-human subject as a powder or in a liquid formulation. Additionally, or alternatively, a lyophilized water-soluble complex can be formulated as a food additive or as an additive into an animal feed. The PSD must be one that can be solubilized fully or partially in either 95% ethanol, an aqueous ethanol solution of 50% ethanol or greater (e.g., 50%, 55%, 60%, 70%, 80%, 85% 90%, 91%, 92%, 93%, 94%, and 95% spectrophotometric grade ethanol) in the presence of a sugar. Preferably, the PSD and sugar optionally having the pharmaceutically acceptable acid is solubilized in at least about 85% ethanol. Optionally, the water-soluble complex remains soluble without the formation of a precipitate for at least 24 hours after formation.

[0070] If desired, a polyethylene glycol (PEG) can be optionally added to the liquid and powdered formulations to further improve bioavailability. Typically, this is between 2,000 and 6,000 Daltons, between 3,000 and 4,500, or between 3,200 and 3,700 as well as other pharmaceutically acceptable molecular weights utilized when formulating PEG with a chemical compound. Popular commercially available PEG forms have a molecular weight of 3350, 4000, and 6000 Daltons. The preparation of PEG may be polydisperse or monodisperse, for example. If polydisperse, then the molecular weight describes the weighted average molecular weight of the preparation. According to the formulations in powder or liquid form, the weight ratio of PEG to a compound may range between and including about 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1. In one embodiment, the weight ratio is about 8:1.

[0071] For administration, the powdered form may be reconstituted in a liquid vehicle, either at the point of manufacture, at the dispensing pharmacy, or by the patient. The liquid vehicle may be water, a buffered aqueous solution, a syrup, or an aqueous beverage, such as an energy drink or an electrolyte-rich drink. For example, the sugar-PSD having improved solubility can be reformulated into sterile saline, or another sterile liquid carrier for administration to a subject as an eye drop or via subcutaneous (s.c.), intraperitoneal (i.p.), intramuscular (i.m.), intravenous (i.v.), oral routes (oral to enter the gastrointestinal tract or for buccal or sublingual administration), or topical routes (e.g., cutaneous applications). Thesugar-drug compound can also be formulated into a metered nasal spray or delivered by subcutaneous or intramuscular injection.

[0072] Suitable ingredients for formulating a tablet or pill or another solid oral form of the water-soluble complex may include any or all of, for example, com starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, and hypromellose. Additional compositions incorporating the described hydrogen-bonded and / or inclusion complex sugar-drug compounds can include formers, oral stool softeners, oral stimulants, and / or rectal suppositories.

[0073] While the dissolution of the water-soluble complex is slow enough to allow for the drug to move into the small intestine without precipitating in the stomach, additional means of extending drug release are known, such as enteric coated tablets, additionally coating the complexes with a slowly dissolving polymer wherein the polymer can be selected by a desired length and / or thickness that can vary the drug release rate, placing the complex in a gelative capsule, placing the complex into an insoluble matrix (e.g., Slow-K or Imdur Durules), placing the complex into an eroding matrix (e.g., MST Continus, Phyllocontin Continus), and / or enclosing the complex in a semi-permeable membrane. See, e.g., June 2011 “Pharmaceutical Issues when Crushing, Opening or Splitting Oral Dosage Forms,” by the Royal Pharmaceutical Society. Additional modified-release oral dosage forms include: “extended-release drug products” wherein a dosage form of the complex allows at least a twofold reduction in dosage frequency as compared to that drug complex being presented without the extended-release format. Examples of extended-release dosage forms include controlled-release, sustained- release, and / or long-acting drug products. Another modified-release oral dosage is a delayed- release drug product. In the delayed release form, the dosage form of the water-soluble complex releases a discrete portion or discrete portions of the drug at a given time other than promptly after administration. Enteric-coated dosage forms are common delayed-release products (e.g., enteric-coated aspirin and other NSAID products). Another modified-release oral form of the water-soluble complex contemplated is a targeted-release drug product. A dosage form that releases the drug from the water-soluble complex at and / or near the intended physiologic site of action. Another modified-release oral dosage of the water-soluble complex is orally disintegrating tablets (ODT) or equivalent. ODT has been developed to disintegrate rapidly in the saliva after oral administration. An ODT form of the water-soluble complex may be used without the addition of water. The water-soluble complex is dispersed in saliva and swallowed with little or no water.

[0074] A “stable” sugar-drug compound is a water-soluble complex (i.e., [DT G]pDrug) prepared by the methods described herein that can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow the use of the compound for the purposes described herein (e.g., therapeutic administration to a subject).

[0075] Any of the components can be packaged in a kit, either separately in individual vessels, or in admixtures with each other. The end user may reconstitute the components with an included diluent or with a diluent of her choosing. The kit, in addition to the components, either separately or in mixtures, may contain instructions for use, tools for mixing and / or administering, storage vessels, etc.

[0076] By a “pharmaceutically acceptable salt” is meant a salt used in a medicine that is approved by the U.S. FDA or the European Medicines Agency (EMA). The use of a pharmaceutically acceptable salt as used in the methods described herein is to improve the solubility of the sugar and insoluble drug.

[0077] Pharmaceutically acceptable acids include l-hydroxy-2-naphthoic acid; 2,2- dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4- acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10- sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane- 1 ,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene- 1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid. See e.g., P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts Weinheim / Zurich:Wiley-VCH / VHCA, 2002.

[0078] By a “pharmaceutically acceptable composition” is meant a composition comprising the water-soluble complex and one or more of a carrier, excipient (e.g., gelatin,cellulose, cellulose derivatives, polyvinylpyrrolidone, a starch, sucrose, and PEG), stabilizer (e.g., glycine, vitamin E, carboxymethylcellulose, sodium lauryl sulfate), a thickener, and a further sweetener. The composition can be a solid or a liquid form.

[0079] By a ‘ ‘cosmetic composition” is meant a composition that is safe to use topically for the treatment of skin conditions such as wrinkling, aging, skin tone, and the like.

[0080] By “a salt” as used to admix with the formed water-soluble complex is meant to include KC1 and HC1. A salt includes sodium chloride (NaCl) and potassium chloride (KC1). The addition of a salt is in an amount sufficient to enhance a subject’s absorption of a water- soluble pharmaceutical. Sodium and potassium play important roles in the body's hydration process by acting as a magnet to draw water into cells, a key factor in maintaining proper hydration. This mechanism ensures that water moves effectively in and out of cells to support essential bodily functions.

[0081] By “improved solubility” of a drug is meant an improvement of the drug’s solubility in water when in the form of a complex over the solubility of the drug when not complexed with the sugar, wherein the sugar-drug complex is formed by the methods described herein. Solutes used to solubilize the compound and sugar can be methanol at 80% methanol, 95% (ACS grade), absolute methanol, or greater, as well as combinations of methanol and ethanol or methanol and water. Combinations can also be used or contain hexane. In a further embodiment, the solvent, or solvent combination, may be water, ethanol, DSMO, DMF, methanol, acetone, chloroform, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, or toluene. After solubilizing the sugar and the compound in ethanol or aqueous ethanol, the ethanol (or other solvent) is evaporated for example under a high rotary vacuum. The solubilized sugar and compound can be solubilized in any of the described solvents, and then dried as described herein. The powder resulting from the evaporation step can be then resolubilized (dissolved) in water. As above, improvements in water solubility of the compound now in the form of the complex are measured at about 20 °C.

[0082] By “a pharmaceutically acceptable composition” is meant a composition comprising the water-soluble sugar-drug complex and one or more of a carrier, excipient (e.g., gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, a starch, sucrose, and PEG), stabilizer (e.g., glycine, vitamin E, carboxymethylcellulose, sodium lauryl sulfate), a thickener, and a further sweetener. The composition can be a solid or a liquid form. Thesecompositions having additional components do not include the components in the complex, but rather in an admixture.

[0083] By the terms “water-soluble complex” and “water-soluble drug complex” are meant to include a sugar (i.e., rubusoside, stevia, dulcoside B, stevioside, n-dodecyl-P-D- maltoside, or rebaudioside A) and a poorly water-soluble drug, e.g., idebenone, as discussed herein that through dissolution with 95% ethanol, optionally with a pharmaceutically acceptable acid or base, forms a complex, optionally further having been solubilized in the presence of a pharmaceutically acceptable acid.

[0084] The use of a mole ratio of PSD to a sugar is used herein. A range of moles of PSD to moles of sugar is 1:1 to 1 : 12, or 1:1 to 1 : 10, or 1:1 to 1 :5, or any 0.1 amount between 1:1 and 1:12.

[0085] By “daily unit dose” is meant the total amount of a compound given daily to a subject, whether in one administration or over multiple administrations, and, when one administration is used, whether one or multiple formulations are used. A dosage of a formulation comprising the compound (e.g., as the water-soluble complex) would contain no more than a Generally Recognized as Safe (GRAS) amount of any constituent of the formulation. For example, in the case of a steviol sugar used as the DTG, a dosage would provide no more than about 10 mg / kg of the steviol sugar, because more than that for an average male of 70 kg, would result in a dosage of 700 mg of the sugar administered in one dosage. In another embodiment, the dosage would provide no more than 5.0 mg / kg of the steviol sugar to the subject. Also contemplated are 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, and 6.0 mg / kg amount of steviol sugar per dosage.

[0086] The term “treating” or “treatment” is meant to include the treatment of a subject who may have Alzheimer’s disease and cognitive disorders, a liver disease, heart disease, Leber’s hereditary optic neuropathy, mitochondrial encephalomyopathies, Friedreich’s ataxia or a dermatological condition that can be benefited by the administration of idebenone as formulated in the complexes described herein. Idebenone is known to reduce oxidative damage and to improve ATP production and therefore can be used to treat a subject who needs improved ATP production and / or to reduce oxidative damage. The subject can be a human.

[0087] By the term “subject” or “animal” as used herein is generally contemplated as a human or primate.

[0088] The water-soluble complex can be admixed with a pharmaceutically acceptable carrier preparation. A pharmaceutically acceptable carrier for topical administration includes sterile, aqueous, or non-aqueous solutions, suspensions, and emulsions. Aqueous carriers for use in a liquid formulation containing the water-soluble complex include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline or buffered media. A pharmaceutically acceptable carrier for parenteral administration includes sterile, aqueous, or non-aqueous solutions, suspensions, and emulsions. Aqueous parenteral vehicles for delivering the water-soluble complex include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.

[0089] The water-soluble complex may be mixed with other pharmaceutically acceptable excipients that are pharmaceutically acceptable and are compatible with the active ingredient in the drug. Suitable pharmaceutically acceptable excipients include water, saline, dextrose, glycerol, and ethanol, or combinations thereof. Intravenous vehicles for use in delivering the water-soluble complex include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like.

[0090] The water-soluble complex can optionally include a preservative and / or an additive. Preservatives and additives contemplated for use with the water-soluble complex can include antimicrobials, anti-oxidants, chelating agents, inert gases, and the like. The preservative and / or additive is admixed with the water-soluble complex after the formation of the complex.

[0091] By the terms “poorly water-soluble drug”, “PSD”, and “drug compound” are meant a regulatory authority- approved drug that has a water solubility when used alone of no more than 10 mg / mL in distilled water. A regulatory authority-approved drug can be a drug approved by the U.S. FDA, U.S. Department of Agriculture (USDA), and / or EMA.

[0092] Another characteristic that may be imparted by the method of improving a drug / compound’ s solubility is that the storage stability of the sugar-compound can be increased.

[0093] The above disclosure generally describes the materials and methods for making compounds such as drugs more soluble through sugars. The scientific principles behind the chemical interactions of a sugar compound and a drug compound are discussed herein. A more complete understanding can be obtained by reference to the following specific examples which are provided herein for purposes of illustration only, and are notintended to limit the scope of the methods and compositions described herein. The amounts of the sugar (DTG) used in the examples are also amounts that can be claimed and should not be excluded from claiming merely because the amount is cited in an example.

[0094] In all the following examples, the same conditions were used unless otherwise noted. The water used is deionized, distilled water. Water can be distilled or deionized water. Unless indicated otherwise, 95% ethanol (ACS spectrophotometric grade, unless otherwise specified) was used. High vacuum drying was performed at room temperature, using, for instance, an Edvards Model RV8 high vacuum pump with an IKA model C-mag HS7 magnetic stirrer. Ethanol can be removed by use of, for example, a Heto Drywinner model #DW-1.0-60E freeze-drying machine. A rotary evaporator such as a Heidolph Basis Hei-VAP value (No. 560-00000-01-1) can alternatively be used to remove ethanol from the mixture, for instance, under reduced pressure at 35 °C bath temperature to produce the solid.EXAMPLE - Idebenone and Stevioside

[0095] The following example indicates that stevioside, a representative DTG, significantly improves the solubility of idebenone.

[0096] Step 1 : In an oven dried single neck RB flask equipped with magnetic stir and septa (flask cap), 5 milligrams (mg) idebenone (0.01478 mmol) and 119 mg stevioside (0.1478 mmol) (molar ratio of 1:10 idebenone to stevioside) were weighed into the RB flask and dissolved in 2.0 ml absolute ethanol (spectrophotometric grade, 95%) at ambient temperature. The reaction mixture was vigorously stirred at room temperature for up to 30 min. The resulting solution was a clear, amber solution with a pH of about 5.6. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C bath temperature resulting in an off-white solid. The off-white solid was dried using vacuum drying performed at room temperature and a high vacuum pump for about one hour to remove the ethanol (EtOH) completely using an Edvards Model # RV8 magnetic stirrer, IKA Model C-MAG HS7 rotary evaporator, a Heidolph type Basis Hei-VAP Value, No. 560-00000-0101. The high vacuum pump was connected to a cooling trap and the trap was connected to the RB flask. Vacuum strength was about 1 mm Hg.

[0097] Step 2: 2.5 mg of the obtained off-white solid (1:0:10.0 molar ratio idebenone: stevioside complex) was then dissolved in 0.3 mL distilled water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambienttemperature for 30 min. The resulting solution (pH~6.0) was clear amber and homogenous by eye.

[0098] The resulting white solid was dissolved in deionized water and then was analyzed by NMR. The NMR analysis confirmed the solubility of the idebenone and stevioside at the 1 :0: 10.0 molar ratio; the process produced an idebenone: stevioside complex. These data indicate that idebenone is soluble in water in the presence of stevioside.EMBODIMENTS

[0099] The following embodiments are contemplated:

[0100] Embodiment 1. A water-soluble aggregate (complex) comprising a nonnutritive sugar and a poorly water-soluble drug (PSD), which aggregate (complex) comprises: a molar ratio of up to about 12 moles of the non-nutritive sugar for each mole of said poorly water-soluble drug, wherein the non-nutritive sugar is one or more of rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A, and wherein the PSD is idebenone, provided that said water-soluble aggregate (complex) has at least a five (5) fold increase in the water solubility of said poorly soluble drug at 20° C as compared to the water solubility of said drug not in said water-soluble aggregate (complex); and further provided that a maximum amount of the non-nutritive sugar in a daily unit dose of said aggregate (complex) is no more than about 10 mg / kg.

[0101] Embodiment 2. The water-soluble aggregate (complex) of Embodiment 1, wherein the non-nutritive sugar is rubusoside, rebaudioside A, dodecyl-P-D-maltoside, dulcoside B, or stevioside.

[0102] Embodiment 3. The water-soluble aggregate (complex) of Embodiment 2, wherein the non-nutritive sugar is rubusoside or stevioside.

[0103] Embodiment 4. The water-soluble aggregate (complex) of any of Embodiments 1-3, wherein the amount of the non-nutritive sugar in the daily unit dose is no more than 5 mg / kg.

[0104] Embodiment 5. The water-soluble aggregate (complex) of any of Embodiments 1-3, wherein the amount of the non-nutritive sugar in the daily unit dose is no more than about 280 mg. 1

[0105] Embodiment 6. The water-soluble aggregate (complex) of any of Embodiments 1-3, wherein said water-soluble aggregate (complex) comprises a molar ratio of the PSD to mole of the non-nutritive sugar of about 1:1 to about 1:10 moles.

[0106] Embodiment 7. The water-soluble aggregate (complex) of any of Embodiments 1-3, wherein said water-soluble aggregate (complex) comprises a molar ratio of about 2 to about 10 moles of the non-nutritive sugar for each mole of said PSD.

[0107] Embodiment 8. The water-soluble aggregate (complex) of Embodiment 7, wherein said water-soluble aggregate (complex) comprises a molar ratio of about 3 moles of the non-nutritive sugar for each mole of said PSD.

[0108] Embodiment 9. The water-soluble aggregate (complex) of any of Embodiments 1-3, wherein said PSD is stable in water at pH 8.5 for at least 2 hours.

[0109] Embodiment 10. The water-soluble aggregate (complex) of any of Embodiments 1-3, wherein said water-soluble aggregate (complex) is stable in water at pH 4 for at least 2 hours.

[0110] Embodiment 11. A dried form of the water-soluble aggregate (complex) of any of Embodiments 1-10, wherein the dried form is stable at 30°C for at least 90 days.

[0111] Embodiment 12. The water-soluble aggregate (complex) of any of Embodiments 1 to 10, wherein the water-soluble aggregate (complex) is in the form of a liquid, a gel, or an emulsion, or is formulated for parenteral administration.

[0112] Embodiment 13. The water-soluble aggregate (complex) of Embodiment 12, wherein the formulation for parenteral administration is to be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intrathecally, or intravenously, or by metered nasal spray, eye drop, transdermal patch, topical cream or gel.

[0113] Embodiment 14. The water-soluble aggregate (complex) of any of Embodiments 1 to 11, wherein the water-soluble (complex) is in the form of a thin film, an effervescent powder or tablet, a syrup, a solution, an elixir, an emulsion, a chewing gum, a lollipop, a sublingual drop, a soft gel, or a tincture.

[0114] Embodiment 15. The water-soluble aggregate (complex) of any of Embodiments 1 to 11, wherein the water-soluble aggregate (complex) is in the form of a cosmetic or dermatological composition.

[0115] Embodiment 16. The water-soluble aggregate (complex) of Embodiment 15, wherein the water-soluble aggregate (complex) is present in the cosmetic or dermatological composition at from about 0.01% to about 5% total weight percent.

[0116] Embodiment 17. A water-soluble aggregate (complex) comprising a nonnutritive sugar and a poorly water-soluble drug (PSD), which water-soluble aggregate (complex) comprises: a molar ratio of about 1 to 12 moles of the sugar for each mole of said PSD, wherein the sugar is one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-P-D-maltoside (DDM), or stevioside, wherein said PSD is idebenone; wherein said water-soluble aggregate (complex) is stable in water at pH 8.5 and at pH 4.0 for at least 2 hours each; provided that said water-soluble aggregate (complex) has at least a five (5) fold increase in the water solubility of said PSD, at 20° C as compared to the water solubility of said PSD that is not in the water-soluble aggregate (complex); and further provided that a maximum amount of the non-nutritive sugar in a daily unit dose of said water-soluble aggregate (complex) is no more than about 280 mg.

[0117] Embodiment 18. A method of making a water-soluble aggregate (complex) comprising a non-nutritive sugar and a poorly water-soluble drug (PSD), the method comprising the steps of admixing, in at least 85% ethanol, the sugar with the PSD in a molar ratio of from about 1 to about 12 moles of the sugar for each mole of said PSD until solubilized thereby forming the water-soluble aggregate (complex), wherein formation (presence) of the water-soluble aggregate (complex) can be determined by nuclear magnetic resonance spectroscopy, and wherein the sugar is one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-P-D- maltoside (DDM), or stevioside; and wherein the admixing step is optionally performed with a pharmaceutically acceptable acid; and optionally drying the water-soluble aggregate (complex), wherein said PSD is idebenone.

[0118] Embodiment 19. The method of Embodiment 18, wherein the sugar is rubusoside or stevioside.

[0119] Embodiment 20. The method of Embodiment 18, wherein the method further comprises drying the water-soluble aggregate (complex) .

[0120] Embodiment 21. The method of Embodiment 20, wherein the dried water- soluble aggregate (complex) is resolubilized in a liquid.

[0121] Embodiment 22. The method of Embodiment 18, wherein the admixing step is in the presence of a sufficient amount of a pharmaceutically acceptable acid to solubilize the non-nutritive sugar and the PSD rendering a homogeneous and clear reaction mixture.

[0122] Embodiment 23. The method of Embodiment 22, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

[0123] Embodiment 24. The method of Embodiment 18, wherein said formed water- soluble aggregate (complex) comprises a molar ratio of about 1 to about 10 moles of the sugar for each mole of said PSD.

[0124] Embodiment 25. The method of Embodiment 24, wherein the sugar is rubusoside or stevioside.

[0125] Embodiment 26. The method of Embodiment 24, wherein said formed water- soluble aggregate (complex) comprises a molar ratio of about 2 to about 5 moles of the sugar for each mole of said PSD.

[0126] Embodiment 27. The method of Embodiment 26, wherein the sugar is rubusoside or stevioside.

[0127] Embodiment 28. The method of Embodiment 24, wherein said formed water- soluble aggregate (complex) comprises a molar ratio of about 2 to about 4.5 moles of the sugar for each mole of said PSD.

[0128] Embodiment 29. The method of Embodiment 28, wherein the sugar is rubusoside or stevioside.

[0129] Embodiment 30. The method of Embodiment 24, wherein said formed water- soluble aggregate (complex) comprises a molar ratio of about 8 moles of the sugar for each mole of said PSD.

[0130] Embodiment 31. The method of Embodiment 30, wherein the sugar is rubusoside or stevioside.

[0131] Embodiment 32. The method of Embodiment 18, wherein said formed water- soluble aggregate (complex) is stable in water at pH 8.5 for at least 2 hours.

[0132] Embodiment 33. The method of Embodiment 18, wherein said formed water- soluble aggregate (complex) is stable in water at pH 4 for at least 2 hours.

[0133] Embodiment 34. The method of Embodiment 21, wherein said method further comprises drying the water-soluble aggregate (complex) by freeze-drying or lyophilizing.

[0134] Embodiment 35. The method of Embodiment 34, wherein the dried water- soluble aggregate (complex) is formulated into a pharmaceutically acceptable liquid or a pill.

[0135] Embodiment 36. A method for reducing skin wrinkles said method comprising administering a composition of any of Embodiments 1 to 17 to a subject having skin wrinkles.

[0136] In further embodiments, the following water-soluble complexes, methods of preparing water-soluble complexes, and methods of the use of water-soluble complexes are contemplated:

[0137] Embodiment 1A. A water-soluble complex comprising a non-nutritive sugar and a drug compound, which water-soluble complex comprises: a molar ratio of up to about 12 moles of the non-nutritive sugar for each mole of said drug compound, wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A, provided that said water-soluble complex has at least about a two-fold increase in the water solubility of said drug compound at 20 °C as compared to the water solubility of said drug compound when not in said water-soluble complex, and / or a maximum amount of the non-nutritive sugar in a daily unit dose of said water-soluble complex is no more than about 10 mg / kg, and wherein the drug compound is idebenone.

[0138] Embodiment 2A. A water-soluble complex comprising a surfactant, and a drug compound (“Drug”) of either Formula (II) or Formula (III) below:[PSS]pDrug (II) or[PXS]pDrug (III) wherein the surfactant is a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), p can be a number from 1 to 5 and the drug compound is idebenone, and the water- soluble complex is formed by admixing the surfactant and the drug compound in a solvent until solubilized, optionally in the presence of a pharmaceutically acceptable acid, thereby forming the water-soluble complex, and drying the solvent from the drug compound and the surfactant, dissolving the dried idebenone and surfactant in water and optionally in a pharmaceutically acceptable acid, wherein the idebenone in the water-soluble complex has an increased water solubility at 20 °C than idebenone not in the water-soluble complex.

[0139] Embodiment 3A. A water-soluble complex comprising a non-nutritive sugar, a surfactant, and a drug compound, said water-soluble complex comprises: a molar ratio of up to about 12.0 moles of the non-nutritive sugar and up to about 12.0 moles of the surfactant, for each mole of the drug compound, wherein the surfactant is a polysorbate or a poloxamer surfactant, wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A, wherein the polysorbate surfactant is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80, or wherein the poloxamer surfactant is Poloxamer 188 (P188), optionally said water-soluble complex has at least a two-fold increase in the water solubility of said drug compound in the form of the water-soluble complex at 20 °C as compared to the water solubility of said drug compound not in said water-soluble complex; and the water-soluble complex contains the non-nutritive sugar at a maximum of no more than about 10.0 mg / kg subject weight in a daily unit dose of the water-soluble complex, and the drug compound is idebenone.

[0140] Embodiment 4A. A water-soluble complex comprising a non-nutritive sugar, a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), and a drug compound, wherein saidwater-soluble complex comprises: a molar ratio of about 1 to 12 moles of the non-nutritive sugar and about 0.5 to 12.0 moles of the PSS or PXS, for each mole of said drug compound, wherein the sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80 and the poloxamer surfactant is Poloxamer 188; the drug compound is idebenone, wherein said water-soluble complex is stable in water at about pH 8.5 or at about pH 4.0 for at least 2 hours; and the non-nutritive sugar is present in a maximum amount in a daily unit dose of said water-soluble complex at no more than about 280.0 mg.

[0141] Embodiment 5A. A water-soluble complex comprising a non-nutritive sugar and a drug compound, which water-soluble complex comprises: a molar ratio of about 1 to 12 moles of the non-nutritive sugar for each mole of said drug compound, wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; wherein said water-soluble complex is stable in water at pH 8.5 and / or at pH 4.0 for at least 2 hours each; optionally or additionally said water-soluble complex has at least about a two-fold increase in the water solubility of said drug compound at 20 °C as compared to the water solubility of said drug compound that is not in the water-soluble complex; and provided that a maximum amount of the non-nutritive sugar in a daily unit dose of said water-soluble complex is no more than about 280 mg, and wherein said drug compound is idebenone.

[0142] Embodiment 6A. A method of making a water-soluble complex comprising a non-nutritive sugar and a drug compound, the method comprising the steps of:admixing from about 1 to about 12 moles of the non-nutritive sugar for each mole of said drug compound in one or more solvents until solubilized, optionally with a pharmaceutically acceptable acid, thereby forming the water-soluble complex, wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D- maltoside, stevioside, or rebaudioside A; and drying the solvent from the drug compound and non-nutritive sugar, dissolving the dried drug compound and non-nutritive sugar in water optionally with a pharmaceutically acceptable acid, wherein a presence of the water-soluble complex is determinable by nuclear magnetic resonance (NMR) spectroscopy, and wherein said drug compound is idebenone.

[0143] Embodiment 7A. A method of making a water-soluble complex comprising a non-nutritive sugar, a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), and a drug compound, the method comprising the steps of: admixing the non-nutritive sugar, the PSS or PXS, and the drug compound in a solvent, wherein the drug compound is in a molar ratio of from about 1 to about 20 moles of the non- nutritive sugar and about 0.5 to about 12.0 moles of the PSS or PXS for each mole of said drug compound until solubilized optionally in the presence of a pharmaceutically acceptable acid, thereby forming the water-soluble complex; drying the solvent from the non-nutritive sugar, PSS or PXS, and drug compound; dissolving said dried non-nutritive sugar, PSS or PXS, and drug compound in water optionally in the presence of a pharmaceutically acceptable acid; wherein a presence of the water-soluble complex is determinable by nuclear magnetic resonance spectroscopy (NMR); the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; and the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80 and the poloxamer surfactant is Poloxamer 188; and the drug compound is idebenone.

[0144] Embodiment 8A. A method of making a water-soluble complex comprising a non-nutritive sugar and a drug compound, the method comprising the steps ofadmixing the non-nutritive sugar and the drug compound in a solvent in a molar ratio of from about 2 to about 20 moles of the non-nutritive sugar for each mole of said drug compound until solubilized, optionally in the presence of a pharmaceutically acceptable acid, thereby forming the water-soluble complex; drying the solvent from the drug compound and non-nutritive sugar; dissolving the dried drug compound and non-nutritive sugar in water and optionally in a pharmaceutically acceptable acid, and wherein a presence of the water-soluble complex is determinable by nuclear magnetic resonance (NMR) spectroscopy; wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; and the drug compound is idebenone.

[0145] Embodiment 9A. A method of making a water-soluble complex comprising a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS) and a drug compound (Drug), the method comprising the steps of: admixing the PSS or PXS and drug compound according toFormula II [PSS]pDrug, orFormula III [PXS]pDrug, wherein p is 0.5 to about 12.0 moles of the PSS or PXS for each mole of said drug compound until solubilized, optionally in the presence of a pharmaceutically acceptable acid, thereby forming the water-soluble complex; drying said solvent from said admixed PSS or PXS and drug compound; dissolving said admixed PSS or PXS and drug compound in water, optionally in the presence of a pharmaceutically acceptable acid; wherein a presence of the water-soluble complex is determinable by nuclear magnetic resonance spectroscopy (NMR); the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80, and the poloxamer surfactant is Poloxamer 188; and the drug compound is idebenone.

[0146] Embodiment 10A. The water-soluble complex of any one of Embodiments 2A to 4A or produced by the method of Embodiment 7 A or 9 A, wherein the polysorbatesurfactant is Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80.

[0147] Embodiment 11 A. The water-soluble complex of Embodiment 3A or 4A or produced by the method of Embodiment 7A or 9A, wherein said water-soluble complex comprises a molar ratio of the drug compound to mole of non-nutritive sugar to mole of polysorbate surfactant (Drug: sugar: PS S) of about 1:1:1 to about 1:10:10 moles.

[0148] Embodiment 12A. The water-soluble complex of Embodiment 3A or 4A or produced by the method of Embodiment 7A or 9A, wherein said water-soluble complex comprises a molar ratio of about 2.0 to about 10.0 moles of the non-nutritive sugar and about 2.0 to about 10.0 moles of the PSS, for each mole of said drug compound (from about 1:2:2 to about 1:10:10 molar ratio of Drug:sugar:PSS).

[0149] Embodiment 13A. The water-soluble complex of Embodiment 12A, wherein said water-soluble complex comprises a molar ratio of about 3.0 moles of the non- nutritive sugar and about 5.0 moles of the PSS for each mole of said drug compound (about 1:3:5 molar ratio of Drug:sugar:PSS).

[0150] Embodiment 14A. The water-soluble complex of any one of Embodiments 2A to 4A or produced by the method of any one of Embodiments 7 A or 9 A, wherein the poloxamer surfactant is Poloxamer 188.

[0151] Embodiment 15 A. The water-soluble complex of any one of Embodiments 3A-4A or produced by the method of Embodiment 7A or 9A, wherein said water-soluble complex comprises a molar ratio of the drug compound to mole of non-nutritive sugar to mole of poloxamer surfactant (Drug:sugar:PXS) of about 1:1.0:0.5 to about 1:12.0:5.0 moles.

[0152] Embodiment 16A. The water-soluble complex Embodiment 15A, wherein said water-soluble complex comprises a molar ratio of about 4.0 to about 12.0 moles of the non-nutritive sugar and about 0.50 to about 3.0 moles of the PXS, for each mole of said drug compound (from about 1:4.0:0.5 to about 1:12.0:3.0 molar ratio of Drug:sugar:PXS).

[0153] Embodiment 17A. The water-soluble complex of Embodiment 16A, wherein said water-soluble complex comprises a molar ratio of about 12.0 moles of the non- nutritive sugar and about 3.0 moles of the PXS for each mole of said drug compound (about 1:12.0:3.0 molar ratio of Drug:sugar:PXS).

[0154] Embodiment 18 A. The water-soluble complex of any one of Embodiments1A and 3A-5A or produced by the method of any one of Embodiments 7 A- 8 A, wherein the non-nutritive sugar is rubusoside, rebaudioside A, dodecyl-P-D-maltoside, dulcoside B, or stevioside.

[0155] Embodiment 19A. The water-soluble complex of Embodiment 18A, wherein the non-nutritive sugar is rubusoside or stevioside.

[0156] Embodiment 20 A. The water-soluble complex of Embodiment 18A, wherein the amount of the non-nutritive sugar in a daily unit dose is no more than 5 mg / kg subject weight.

[0157] Embodiment 21 A. The water-soluble complex of Embodiment 18A, wherein the amount of the non-nutritive sugar in a daily unit dose is no more than about 280 mg.

[0158] Embodiment 22A. The water-soluble complex of any one of Embodiments 1 A, and 3A-5A, or produced by the method of any one of Embodiments 6A-8A, wherein said water-soluble complex comprises a molar ratio of the drug compound to mole of the non- nutritive sugar of about 1:1 to about 1:10 moles.

[0159] Embodiment 23A. The water-soluble complex of any one of Embodiments 1A-3A or produced by the method of any one of Embodiments 5A-9A wherein said water- soluble complex comprises a molar ratio of about 2 to about 10 moles of the non-nutritive sugar for each mole of said drug compound.

[0160] Embodiment 24A. The water-soluble complex of Embodiment 23A, wherein said water-soluble complex comprises a molar ratio of about 3 moles of the non- nutritive sugar for each mole of said drug compound.

[0161] Embodiment 25A. The water-soluble complex of any of Embodiments 1A- 5A or produced by the method of any of Embodiments 6A-9A, wherein said drug compound is stable in water at pH 8.5 for at least 2 hours.

[0162] Embodiment 26A. The water-soluble complex of any one of Embodiments 1A-5A or produced by the method of any one of Embodiments 6A-9A, wherein said water- soluble complex is stable in water at pH 4 for at least 2 hours.

[0163] Embodiment 27A. A dried form of the water-soluble complex of any one of Embodiments 1 A-5A or produced by the method of any one of Embodiments 6A-9A, wherein the dried form is stable at 30 °C for at least 90 days.

[0164] Embodiment 28A. The water-soluble complex of any one of Embodiments 1A-5A or produced by the method of any one of Embodiments 6A-9A, wherein the water- soluble complex is formulated as a liquid, a gel, an emulsion, or formulated for parenteral administration.

[0165] Embodiment 29A. The water-soluble complex of Embodiment 28A, wherein the water-soluble complex is formulated for parenteral administration to be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intrathecally, or intravenously, or via metered nasal spray, eye drop, transdermal patch, topical cream or gel.

[0166] Embodiment 30A. The water-soluble complex of any one of Embodiments 1A-5A or produced by the method of any one of Embodiments 6A-9A, wherein the water- soluble complex is is formulated as a thin film, an effervescent powder or tablet, a syrup, a solution, a wash, a stick, an elixir, an emulsion, a chewing gum, a lollipop, a sublingual drop, a soft gel, or a tincture.

[0167] Embodiment 31 A. The water-soluble complex of any one of Embodiments 1A-5A or produced by the method of any one of Embodiments 6A-9A, wherein the water- soluble complex is in the form of a cosmetic or dermatological composition and optionally comprising a salt.

[0168] Embodiment 32A. The water-soluble complex of Embodiment 31 A, wherein the water-soluble complex is present in the cosmetic or dermatological composition at from about 0.01% to about 5% total weight percent.

[0169] Embodiment 33A. The method of any one of Embodiments 6A-9A, wherein the method further comprises a pharmaceutically acceptable acid.

[0170] Embodiment 34A. The method of Embodiment 33A, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

[0171] Embodiment 35A. The method of any one of Embodiments 6A-9A or 33A, wherein the solvent is selected from one or more of ethanol, methanol, hexane, dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetone, ethyl acetate, hexane, heptane, dichloromethane, tetrahydro furan, acetonitrile, toluenechloroform, isopropanol, 1- propanol, 2-propanol (isopropyl alcohol), or xylene or any combination thereof.

[0172] Embodiment 36A. A method for reducing skin wrinkles in a subject said method comprising administering a composition comprising the water-soluble complex of any one of Embodiments 1A-5A or produced by a method of any one of Embodiments 6A-9A to the subject in need thereof.

[0173] Embodiment 37A. A method for treating a cognitive disorder or Leber’s hereditary optic neuropathy in a subject comprising administering a composition comprising the water-soluble complex of any one of Embodiments 1 A-5A or produced by a method of any one of Embodiments 6A-9A to the subject in need thereof.

[0174] Embodiment 38A. A method of treating a condition, said method comprising administering to a subject a pharmaceutically acceptable composition comprising the water-soluble complex of any one of Embodiments 1A-5A or produced by the method of any one of Embodiments 6A-9A, wherein said condition is a cognitive disorder, Friedreich’s ataxia, a migraine, post-stroke epilepsy, a skin condition, or Leber’s hereditary optic neuropathy.

[0175] Embodiment 39A. The method of any one of Embodiments 37A-39A, wherein the water-soluble complex comprising a dosage form of about 150 mg or less idebenone in the water-soluble complex.

[0176] Embodiment 40A. Use of the water-soluble complex of any one of Embodiments 1A-5A or produced by the method of any one of Embodiments 6A-9A for the manufacture of a medicament for treating a cognitive disorder, Friedreich’s ataxia, a migraine, post-stroke epilepsy, a skin condition, or Leber’s hereditary optic neuropathy.

[0177] Embodiment 41A. A composition for reducing wrinkles and skin aging comprising the water-soluble complex of any one of Embodiments 1 A to 27A and a salt.

[0178] Embodiment 42A. The composition of Embodiment 41A further comprising one or more skin-hydration components, a skin-firming component, a skin-smoothing component skin tone evening agent, a moisturizer, a vitamin, an anti-oxidant, glycerin, fragrance, colors, and stabilizers and is formulated into a wash, lotion, cream, stick or serum.

[0179] Embodiment 43A. A pharmaceutically acceptable composition comprising the water-soluble complex of any one of Embodiments 1A to 27A, a pharmaceutically acceptable carrier or excipient, and a salt.

Claims

CLAIMS1. A water-soluble complex comprising a non-nutritive sugar and a drug compound, which water-soluble complex comprises: a molar ratio of up to about 12 moles of the non-nutritive sugar for each mole of the drug compound, wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A, provided that the drug compound in the water-soluble complex has at least about a twofold increase in water solubility compared to the drug compound at 20 °C as compared to the water-soluble complex when not in the water-soluble complex, and / or a maximum amount of the non-nutritive sugar in a daily unit dose of the water-soluble complex is no more than about 10 mg / kg, and wherein the drug compound is idebenone.

2. A water-soluble complex comprising a surfactant, and a drug compound (Drug) of either Formula (II) or Formula (III) below:[PSS]pDrug Formula (II) or[PXS]pDrug Formula (III) wherein the surfactant is a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), p can be a number from 1 to 5 and the drug compound is idebenone, and the water- soluble complex is formed by admixing the surfactant and idebenone in a solvent until solubilized, optionally in the presence of a pharmaceutically acceptable acid, thereby forming the water-soluble complex, and drying the solvent from the idebenone and the surfactant, dissolving the dried idebenone and surfactant in water and optionally with a pharmaceutically acceptable acid, wherein the idebenone in the water-soluble complex has an increased water solubility at 20 °C than idebenone not in the water-soluble complex.

3. A water-soluble complex comprising a non-nutritive sugar, a surfactant, and a drug compound, wherein the water-soluble complex comprises:a molar ratio of up to about 12.0 moles of the non-nutritive sugar and up to about 12.0 moles of the surfactant, for each mole of the drug compound, wherein the surfactant is a polysorbate or a poloxamer surfactant, wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A, the polysorbate surfactant is of one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80; or wherein the poloxamer surfactant is Poloxamer 188 (P188), and optionally the drug compound in the water-soluble complex has at least a two-fold increase in the water solubility of the drug compound at 20 °C as compared to the water solubility of the drug compound not in the water-soluble complex; and the water-soluble complex contains the non-nutritive sugar at a maximum of no more than about 10.0 mg / kg subject weight in a daily unit dose of the water-soluble complex, and the drug compound is idebenone.

4. A water-soluble complex comprising a non-nutritive sugar, a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), and a drug compound, wherein the water- soluble complex comprises: a molar ratio of about 1 to 12 moles of the non-nutritive sugar and about 0.5 to 12.0 moles of the PSS or PXS, for each mole of the drug compound, wherein the sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80 and the poloxamer surfactant is Poloxamer 188; the drug compound is idebenone, wherein the water-soluble complex is stable in water at about pH 8.5 or at about pH 4.0 for at least 2 hours; and the non-nutritive sugar is present in a daily unit dose of the water-soluble complex at no more than about 280.0 mg.

5. A water-soluble complex comprising a non-nutritive sugar and a drug compound, which water-soluble complex comprises: a molar ratio of about 1 to 12 moles of the non-nutritive sugar for each mole of the drug compound, wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; wherein the water-soluble complex is stable in water at pH 8.5 and / or at pH 4.0 for at least 2 hours each; optionally or additionally the water-soluble complex has at least about a two-fold increase in the water solubility of the drug compound at 20 °C as compared to the water solubility of the drug compound that is not in the water-soluble complex; and provided the non-nutritive sugar in a daily unit dose of the water-soluble complex is no more than about 280 mg, and the drug compound is idebenone.

6. A method of making a water-soluble complex comprising a non-nutritive sugar and a drug compound, the method comprising the steps of: admixing from about 1 to about 12 moles of the non-nutritive sugar for each mole of the drug compound in one or more solvents until solubilized, optionally with a pharmaceutically acceptable acid, thereby forming the water-soluble complex, wherein the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D- maltoside, stevioside, or rebaudioside A; and drying the solvent from the drug compound and non-nutritive sugar, dissolving the dried drug compound and non-nutritive sugar in water optionally with a pharmaceutically acceptable acid, wherein a presence of the water-soluble complex is determinable by nuclear magnetic resonance (NMR) spectroscopy, and wherein the drug compound is idebenone.

7. A method of making a water-soluble complex comprising a non-nutritive sugar, a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), and a drug compound, the method comprising the steps of: admixing the non-nutritive sugar, the PSS or PXS, and the drug compound in a solvent, wherein the drug compound is in a molar ratio of from about 1 to about 20 moles of the non-nutritive sugar and about 0.5 to about 12.0 moles of the PSS or PXS for each mole of the drug compound until solubilized, optionally in the presence of a pharmaceutically acceptable acid, thereby forming the water-soluble complex; drying the solvent from the admixed non-nutritive sugar, PSS or PXS, and drug compound; dissolving the dried non-nutritive sugar, PSS or PXS, and drug compound in water, optionally in the presence of a pharmaceutically acceptable acid; wherein a presence of the water-soluble complex is determinable by nuclear magnetic resonance spectroscopy (NMR); the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; and the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80 and the poloxamer surfactant is Poloxamer 188; and the drug compound is idebenone.

8. A method of making a water-soluble complex comprising a non-nutritive sugar and a drug compound, the method comprising the steps of admixing the non-nutritive sugar and the drug compound in a solvent in a molar ratio of from about 2 to about 20 moles of the non-nutritive sugar for each mole of the drug compound until solubilized, optionally in the presence of a pharmaceutically acceptable acid, thereby forming the water-soluble complex; drying the solvent from the drug compound and non-nutritive sugar; dissolving the dried drug compound and non-nutritive sugar in water and optionally in a pharmaceutically acceptable acid; and wherein a presence of the water-soluble complex is determinable by nuclear magnetic resonance (NMR) spectroscopy; the non-nutritive sugar is one or more of avantame, neotame, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-P-D-maltoside, stevioside, or rebaudioside A; and the drug compound is idebenone.

9. A method of making a water-soluble complex comprising a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS) and a drug compound (“Drug”), the method comprising the steps of:admixing the PSS or PXS and drug compound according toFormula (II) [PSS]pDrug, orFormula (III) [PXS]pDrug, wherein p is 0.5 to about 12.0 moles of the PSS or PXS for each mole of the drug compound until solubilized, optionally in the presence of a pharmaceutically acceptable acid, thereby forming the water-soluble complex; drying the solvent from the PSS or PXS and drug compound; dissolving the dried PSS or PXS and drug compound in water optionally in the presence of a pharmaceutically acceptable acid; wherein a presence of the water-soluble complex is determinable by nuclear magnetic resonance spectroscopy (NMR); the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80, and the poloxamer surfactant is Poloxamer 188; and the drug compound is idebenone.

10. The water-soluble complex of any one of claims 2 to 4 or produced by the method of claim 7 or 9, wherein the polysorbate surfactant is Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80.

11. The water-soluble complex of claim 3 or 4 or produced by the method of any one of claims 7 to 9, wherein the water-soluble complex comprises a molar ratio of the drug compound to mole of non-nutritive sugar to mole of polysorbate surfactant (Drug'. sugar:PSS) of about 1:1:1 to about 1:10:10 moles.

12. The water-soluble complex of claim 3 or 4 or produced by the method of claim 7 or 9, wherein the water-soluble complex comprises a molar ratio of about 2.0 to about 10.0 moles of the non-nutritive sugar and about 2.0 to about 10.0 moles of the PSS, for each mole of the drug compound (from about 1:2:2 to about 1:10:10 molar ratio of DrMg:sugar:PSS).

13. The water-soluble complex of claim 12, wherein the water-soluble complex comprises a molar ratio of about 3.0 moles of the non-nutritive sugar and about 5.0 moles of the PSS for each mole of the drug compound (about 1:3:5 molar ratio of DrMg:sugar:PSS).

14. The water-soluble complex of any one of claims 2 to 4 or produced by the method of claim 7 or 9, wherein the poloxamer surfactant is Poloxamer 188.

15. The water-soluble complex of any one of claims 3-4 or produced by the method of claim 7 or 9, wherein the water-soluble complex has a molar ratio of the drug compound to mole of non-nutritive sugar to mole of poloxamer surfactant (D / i / #: sugar: PXS) of about 1:1.0:0.5 to about 1:12.0:5.0 moles.

16. The water-soluble complex of claim 15, wherein the water-soluble complex has a molar ratio of about 4.0 to about 12.0 moles of the non-nutritive sugar and about 0.50 to about 3.0 moles of the PXS, for each mole of the drug compound (from about 1:4.0:0.5 to about 1:12.0:3.0 molar ratio of DrMg:sugar:PXS).

17. The water-soluble complex of claim 16, wherein the water-soluble complex comprises a molar ratio of about 12.0 moles of the non-nutritive sugar and about 3.0 moles of the PXS for each mole of the drug compound (about 1:12.0:3.0 molar ratio of Drug : sugar: PXS ) .

18. The water-soluble complex of any one of claims 1 and 3-5 or produced by the method of any one of claims 7-8, wherein the non-nutritive sugar is rubusoside, rebaudioside A, dodecyl-P-D-maltoside, dulcoside B, or stevioside.

19. The water-soluble complex of claim 18, wherein the non-nutritive sugar is rubusoside or stevioside.

20. The water-soluble complex of claim 18, wherein the amount of the non-nutritive sugar in a daily unit dose of the water-soluble complex is no more than 5 mg / kg subject weight.

21. The water-soluble complex of claim 18, wherein the amount of the non-nutritive sugar in a daily unit dose of the water-soluble complex is no more than about 280 mg.

22. The water-soluble complex of any one of claims 1 and 3-5 or produced by the method of any one of claims 6-8, wherein the water-soluble complex comprises a molar ratio of the drug compound to mole of the non-nutritive sugar of about 1:1 to about 1:10 moles.

23. The water-soluble complex of any one of claims 1-3 or produced by the method of any one of claims 5-9 wherein the water-soluble complex comprises a molar ratio of about 2 to about 10 moles of the non-nutritive sugar for each mole of the drug compound.

24. The water-soluble complex of claim 23, wherein the water-soluble complex comprises a molar ratio of about 3 moles of the non-nutritive sugar for each mole of the drug compound.

25. The water-soluble complex of any one of claims 1-5 or produced by the method of any one of claims 6-9, wherein the drug compound is stable in water at pH 8.5 for at least 2 hours.

26. The water-soluble complex of any one of claims 1-5 or produced by the method of any one of claims 6-9, wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours.

27. A dried form of the water-soluble complex of any one of claims 1-5 or produced by the method of any one of claims 6-9, wherein the dried form is stable at 30 °C for at least 90 days.

28. The water-soluble complex of any one of claims 1-5 or produced by the method of any one of claims 6-9, wherein the water-soluble complex is formulated as a liquid, a gel, or an emulsion, or is formulated for parenteral administration.

29. The water-soluble complex of claim 28, wherein the water-soluble complex is formulated for parenteral administration to be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intrathecally, or intravenously, or via metered nasal spray, eye drop, transdermal patch, topical cream or gel.

30. The water-soluble complex of any one of claims 1-5 or produced by the method of any one of claims 6-9, wherein the water-soluble complex is formulated as a thin film, an effervescent powder or tablet, a syrup, a solution, a wash, a stick, an elixir, an emulsion, a chewing gum, a lollipop, a sublingual drop, a soft gel, or a tincture.

31. The water-soluble complex of any one of claims 1-5 or produced by the method of any one of claims 6-9, wherein the water-soluble complex is in the form of a cosmetic or dermatological composition.

32. The water-soluble complex of claim 31, wherein the water-soluble complex is present in the cosmetic or dermatological composition at from about 0.01% to about 5% total weight percent.

33. The method of any one of claims 6-9, wherein the method further comprises a pharmaceutically acceptable acid.

34. The method of claim 33, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

35. The method of any one of claims 6-9 or 33, wherein the solvent is selected from one or more of ethanol, methanol, hexane, dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetone, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, toluenechloroform, isopropanol, 1 -propanol, 2-propanol (isopropyl alcohol), or xylene or any combination thereof.

36. A method for reducing skin wrinkles in a subject the method comprising administering a composition comprising the water-soluble complex of any one of claims 1-5 or produced by a method of any one of claims 6-9 to the subject in need thereof.

37. A method for treating a cognitive disorder or Leber’s hereditary optic neuropathy in a subject comprising administering a composition comprising the water-solublecomplex of any one of claims 1-5 or produced by a method of any one of claims 6-9 to the subject in need thereof.

38. A method of treating a condition, the method comprising administering to a subject a pharmaceutically acceptable composition comprising the water-soluble complex of any one of claims 1-5 or produced by the method of any one of claims 6-9, wherein the condition is a cognitive disorder, Friedreich’s ataxia, a migraine, post-stroke epilepsy, a skin condition, or Leber’s hereditary optic neuropathy.

39. The method of any one of claims 37-38, wherein the water-soluble complex is in a dosage form comprising 150 mg or less idebenone in the water-soluble complex.

40. Use of the water-soluble complex of any one of claims 1-5 or produced by the method of any one of claims 6-9 for the manufacture of a medicament for treating a cognitive disorder, Friedreich’s ataxia, a migraine, post-stroke epilepsy, a skin condition, or Leber’s hereditary optic neuropathy.

41. A composition for reducing wrinkles and skin aging comprising the water- soluble complex of any one of claims 1 to 27 and a salt.

42. The composition of claim 41 further comprising one or more skin-hydration components, a skin-firming component, a skin smoothing component, a skin tone evening agent, a moisturizer, a vitamin, an anti-oxidant, glycerin, fragrance, colors, and stabilizers and is formulated into a wash, lotion, cream, stick or serum.

43. A pharmaceutically acceptable composition comprising the water-soluble complex of any one of claims 1-27, a pharmaceutically acceptable carrier or excipient, and a salt.

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