Compositions and methods for improving solubility of anthracyclines

Abstract

A method of preparing a water-soluble complex comprising an anthracycline or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal or polymorph thereof, by mixing the anthracycline with a non-nutritive sugar and / or a surfactant in the presence of a solvent, removing the solvent and dissolving the water-soluble complex in water. Also described are the water-soluble complex and compositions comprising the complex.

Description

Technical Field

[0001] A method for preparing compositions comprising more soluble anthracycline compounds or pharmaceutically acceptable salts thereof is provided, as well as the compositional form produced by the method.

[0002] Reference to relevant applications

[0003] This international application claims the interest in and priority of U.S. Provisional Applications 63 / 589,958 and 63 / 613,443, filed on October 12, 2023 and December 21, 2023, respectively, the entire contents of which are incorporated herein by reference for all purposes.

[0004] background

[0005] The solubility of compounds plays a crucial role in their development, particularly in the pharmaceutical industry. It significantly impacts the efficacy of a compound as a drug in the recipient's body. Poor drug solubility can lead to challenges in drug metabolism, drug permeability, interactions with other drugs, or the need for prolonged drug release. If a drug is insoluble, it may not be fully absorbed into the recipient's bloodstream and could be excreted before reaching the site of action (Ganeosan et al., "Solubility: a speed-breaker on the drug discovery highway,"). Bioequiv. Availab . 3(3): 56-8, 2017, Editorial).

[0006] New methods for identifying compounds that are more soluble will help advance the development of many compounds that would otherwise be denied further drug approval simply because of their insolubility. This approach could allow for the investigation of drugs rejected due to insolubility and accelerate the pace of identification methods to improve the solubility of drugs that have begun or are in clinical trials, as well as pharmaceutical and generic drugs. Summary of the Invention

[0007] This article provides a method for improving the solubility of compounds such as anthracyclines (e.g., doxorubicin or its pharmaceutically acceptable salts) by forming hydrogen bonds between the compound and a non-nutritive sugar. In practice, the method produces a water-soluble complex comprising a non-nutritive sugar and anthracycline.

[0008] The solubility of a compound is often improved by its specific salt form, as well as its hydrates, solvates, eutectics, and polymorphs. This article describes sugars that can be bonded to compounds via hydrogen bonds, said bonding being carried out by methods that allow the sugar-linked compounds to have higher solubility than the compounds alone, and in some cases, higher solubility than the salt forms of the compounds.

[0009] Compounds linked to non-nutritive sugars are usually chemical pharmaceutical compounds.

[0010] One disclosed embodiment is a method for improving the solubility of a compound, comprising: mixing the compound with a sugar in a solvent; and removing the solvent to obtain a powder composition comprising a sugar hydrogen-bonded to the compound. This embodiment includes the compound and sugar being present in a weight ratio of about 1.0:20.0 or from about 1.0 to about 10.0. In another embodiment, the water-soluble complex described herein may be represented by formula I: (I) Wherein sugars (i.e., non-nutritive sugars) and drugs (e.g., anthracyclines) are as defined herein, and p is a number from 1.0 to 20 moles, from 1.0 to 12.0 moles, and any value within that range.

[0011] The water-soluble complex preferably has a water solubility of the drug in the form of a complex that is at least 50% better than that of the drug alone. The improvement in water solubility of the complex can also be two, three, four, or five times that of the drug alone.

[0012] This article also provides water-soluble complexes comprising anthracyclines and surfactants. Surfactant-anthracycline water-soluble complexes can also be formed by including non-nutritive sugars together with surfactants and anthracyclines. A water-soluble complex comprising a non-nutritive sugar, a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), and a pharmaceutical compound, the water-soluble complex comprising the following molar ratio: about 1 to 12 moles of non-nutritive sugar and about 0.5 to 12.0 moles of PSS or PXS per mole of the pharmaceutical compound, wherein the non-nutritive sugar is one or more of ADVANTAME®, NEOTAME®, thaumatin, saccharin, sucralose, loh han guo, aspartame, acetylsupanose potassium, allulose, rubusoside, dulcoside B, lauryl-β-D-maltodextrin, steviol glycoside, or riboboroside 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 formed water-soluble complex is stable in water at approximately pH 8.5 or approximately pH 4.0 for at least 2 hours. The formed water-soluble complex should contain a maximum amount of non-nutritive sugars present in a unit daily dose of the water-soluble complex not exceeding approximately 280.0 mg of sugar.

[0013] In another embodiment, a water-soluble complex of formula (II) or formula (III) comprising a surfactant and a poorly soluble drug (PSD or Drug) can be formed: (Formula II) or 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 anthracycline compound. The water-soluble complex is formed by mixing the surfactant and Drug in a solvent (one or more solvents) optionally in the presence of a pharmaceutically acceptable acid until dissolved, drying the solvent containing the Drug and surfactant, and dissolving the dried Drug and surfactant in water and optionally a pharmaceutically acceptable acid, and wherein the Drug in the form of the water-soluble complex has increased water solubility at 20°C compared to the Drug not in the water-soluble complex. The composition containing the water-soluble complex may further contain a salt, such as NaCl or KCl.

[0014] One embodiment includes using a sugar to bind to a drug via hydrogen bonding in the disclosed method, wherein the sugar may be stevia glycoside, durcuric acid A, durcuric acid B, sucrose, D-fructose, sucralose, riboboroside A, riboboroside B, riboboroside D, stevioside, stevia, n-octyl glucose, n-lauryl-β-D-maltodextrin, ADVANTAME®, NEOTAME®, semathymidine, saccharin, sucralose, stevioside, monk fruit, aspartame, acetylsupan potassium (Ace-K), or allulose.

[0015] The methods disclosed herein use solvents to dissolve sugars and compounds or drugs to generate hydrogen bonds. In one aspect, the solvent may be ethanol, water, hexane, or other pharmaceutically acceptable solvents. A second solvent may be ethanol, water, hexane, or other pharmaceutically acceptable solvents.

[0016] Another embodiment includes a powdered formulation produced by the disclosed method, wherein, taking into account the hydrogen bonding between the sugar and the compound, the powdered formulation has improved solubility characteristics compared to the solubility properties of the compound prior to hydrogen bonding to the sugar. One embodiment includes a water-soluble complex formed by the disclosed method having a weight ratio of the compound to the sugar of about 0.1:1.0 to about 1.0:20.0, or about 1.0:1.0 to about 1.0:20.0, and any 0.1 value between 0.1 and 1:20.0.

[0017] Another embodiment includes a powdered formulation or a sugar-compound hydrogen-bonded formulation being a drug. Exemplary anthracycline compounds used include, but are not limited to, daunorubicin, doxorubicin, epirubicin, edabacin, mitoxantrone, pentorubicin, aldoxorubicin, anamycin, purcamycin, pirarubicin, arubicin, and pharmaceutically acceptable salts thereof.

[0018] Another embodiment includes a powdered formulation suitable for reconstitution in water or saline, wherein when reconstituted in water or saline, the sugar-bonded compound in the formulation has a higher solubility than the compound in the absence of sugars bound to the compound. The water and saline may optionally be sterile. When formulated in sterile water or sterile saline, the reconstituted water-soluble complex may be administered to the subject intravenously, intraperitoneally, intramuscularly, subcutaneously, intranasally, or orally, or sublingually.

[0019] The method may use sugars such as ADVANTAME®, NEOTAME®, semathymose, saccharin, sucralose, monk fruit, aspartame, acetylsupanose potassium, allulose, stevia glycosides, durcuric acid glycoside B, lauryl-β-D-maltose glycoside, steviol glycoside, or ribobadiol glycoside A. In other embodiments, the water-soluble complex comprises a non-nutritive sugar selected from stevia glycosides, ribobadiol glycoside A, lauryl-β-D-maltose glycoside, durcuric acid glycoside B, steviol glycoside, or any combination thereof. In still other embodiments, the complex may be formed using stevia glycosides, durcuric acid glycoside B, lauryl-β-D-maltose glycoside, steviol glycoside, or ribobadiol glycoside A, or any combination thereof. In still other embodiments, the water-soluble sugar-drug complex uses stevia glycosides, steviol glycoside, or combinations thereof.

[0020] In a further embodiment, the amount of non-nutritive sugars such as DTG (or other non-nutritive sugars) in the daily unit dose administered to the subject does not exceed about 5 mg / kg of the subject's body weight. In another embodiment, the water-soluble complex comprises DTG sugar (or other non-nutritive sugars) in an amount not exceeding about 280 mg in the daily unit dose.

[0021] The powdered formulation produced by this method will have sugars that are hydrogen-bonded with another compound.

[0022] The method may further include dissolving the obtained powder in a second solvent and drying the dissolved powder. The second solvent may be ethanol, water, hexane, or a pharmaceutically acceptable solvent. An optional filtration step may be used to remove particulate matter that may be present in this step.

[0023] In one embodiment, the powdered formulation can be reformed into feed, tablets, capsules, capsule-shaped tablets, suppositories, or food additives. Alternatively, the powdered formulation can be reformed into liquids, syrups, gels, or beverages. In another aspect, the powdered compound can be reformed into pills, capsules, tablets, or extended-release compositions for oral administration to a subject.

[0024] Another embodiment includes a kit for preparing a liquid formulation from a powdered formulation, comprising a powdered formulation and a sterile liquid, and optionally instructions for mixing the powdered formulation and the sterile liquid to prepare the liquid formulation.

[0025] Another implementation includes a water-soluble complex that is stable for at least about 2 hours when dissolved in water at pH 8.5.

[0026] In a further embodiment, the water-soluble complex is stable for at least about 2 hours when dissolved in water at about pH 4.

[0027] Another implementation includes that the dried form of the water-soluble complex is stable at 30°C for at least 90 days.

[0028] A further embodiment includes a water-soluble complex that is stable at room temperature for approximately 24 hours. Another embodiment includes a water-soluble complex that does not require refrigeration for at least 24 hours.

[0029] Another embodiment includes a water-soluble complex in the form of a cream, topical cream, ointment, gel, soft gel, syrup, solution, elixir, liquid, emulsion, transdermal patch, or any other formulation suitable for topical application. Another embodiment includes a water-soluble complex in the form of a cosmetic or dermatological composition. Another embodiment includes a cosmetic or dermatological composition wherein the water-soluble complex is present in the cosmetic or dermatological composition at about 0.01% to about 5% w / v (weight of the pharmaceutical compound / volume of the composition) or about 0.01% to about 5% w / v (weight of the water-soluble complex of the pharmaceutical compound / volume of the composition). The dermatological composition may further contain a salt such as NaCl or KCl.

[0030] Alternatively, the water-soluble complex may be in the form of a powder, tablet, orally disintegrating tablet, capsule, film, lozenge, chewable pill or gel, or effervescent powder or tablet. Alternatively, the water-soluble complex may be a formulation prepared for parenteral administration, which can be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intravenously, as a dose-controlled nasal spray or eye drop. Another embodiment includes a water-soluble complex formulated as a film, effervescent powder or tablet, chewable gum, gel, lollipop, sublingual drop, or tincture.

[0031] Another embodiment is a water-soluble complex comprising a sugar and a poorly water-soluble drug, the water-soluble complex comprising: a molar ratio of about 3 moles of non-nutritive sugar per mole of the poorly water-soluble drug, wherein the sugar is one or more of ADVANTAME®, NEOTAME®, semathymidine, saccharin, sucralose, monk fruit, aspartame, acetylsupan potassium, allulose, stevia glycoside, ducresil B, lauryl-β-D-maltodextrin, steviol glycoside, or riboboroside A; wherein the water-soluble complex is stable in water at pH 8.5 and pH 4.0 for at least 2 hours each; provided that the water-soluble complex has an increase in the water solubility of the poorly water-soluble drug by at least about 50% or two, three, four, or five (5) times compared to the water solubility of the poorly water-soluble drug not in the water-soluble complex; and further or optionally, provided that the maximum amount of non-nutritive sugar in a daily unit dose of the water-soluble complex does not exceed about 280 mg.

[0032] Another method includes preparing a water-soluble complex comprising a non-nutritive sugar (or a combination of non-nutritive sugars) and a poorly water-soluble drug (PSD, in this case, anthracycline compound), the method comprising the steps of: mixing the sugar and PSD in at least 85% ethanol (or at least 90% or 95%) at a molar ratio of about 1.0 to about 5.0 moles of non-nutritive sugar per mole of the drug compound (anthracycline compound) until dissolved to form a water-soluble complex, wherein the formation, presence, 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 stevia glycoside, ribobadiol A, durcuryl glycoside B, lauryl-β-D-maltose glycoside (DDM), or steviol glycoside or other non-nutritive sugars listed herein; and wherein the mixing step is optionally carried out with a pharmaceutically acceptable acid; and optionally drying the water-soluble complex. Another method uses stevia glycoside or steviol glycoside as the sugar in the method. The poorly water-soluble drug (i.e., PSD) used in the method for preparing the water-soluble complex can be one or more anthracycline compounds or their pharmaceutically acceptable salts, hydrates, solvates, polymorphs or cocrystals.

[0033] The dissolution method used in the first solvent step or the water step (second step) may optionally include one or more acids or bases to further improve the solubility and / or stability of the drug-sugar complex formed by said method. Preferably, when used with a drug, said acid or base is a pharmaceutically acceptable acid or base. Acids or bases may be added until the solubility of the drug compound and the non-nutritive sugar is achieved.

[0034] For the first step, the pharmaceutical compound can be completely or partially dissolved in 95% ethanol, anhydrous ethanol, or an aqueous solution of 50% or higher ethanol (e.g., 50%, 55%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, and 95% spectrophotometric grade ethanol and anhydrous ethanol) in the presence of a sugar. A combination of ethanol and methanol may also be used. The compound or pharmaceutical compound can be any free form of the compound or its salt, hydrate, or polymorph, or a salt of a specified free form of the pharmaceutical compound. The pharmaceutical compound and sugar are dissolved in at least about 85% ethanol, and optionally in the presence of an acid or base. In another embodiment, methanol may be added to ethanol, the pharmaceutical compound, the sugar, and optionally an acid / base to further dissolve and form a water-soluble complex. Optionally, after the formation of the water-soluble complex, the water-soluble complex remains soluble and does not form a precipitate for at least 24 hours. Alternatively, the solvent can be a co-solvent, such as a binary or ternary (or higher) mixture of solvents. For example, the co-solvent could be about 50% ethanol and the remainder buffer or water, or different or additional solvents could be used in combination with water or a buffered aqueous solution. Generally, a ratio of ethanol to methanol (e.g., 95% or higher methanol) as small as about 1:0.00005 can improve solubility compared to ethanol alone. Therefore, a range is included from 1:1 ethanol to methanol to 1:0.00001 (and all 0.00001 values ​​within that range). In some embodiments, methanol can be used instead of ethanol, such that the methanol to ethanol ratio is the opposite of those cited above (e.g., 1:1 methanol to ethanol to 1:0.00001 methanol to ethanol, and all values ​​included within that range). It can also be a combination of ethanol, methanol, and isopropanol.

[0035] Other pharmaceutically acceptable solvents that can be used alone or in combination to form water-soluble complexes include acetone, acetonitrile, anisole (methoxybenzene), benzene, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, carbon tetrachloride (tetrachloromethane), cumene, cyclohexane, 1,2-dichloroethane, 1,1-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, 2-ethoxyethanol, ethyl acetate, 2-ethyl... Oxyethanol, ethyl acetate, ethylene glycol, diethyl ether, ethyl formate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, 2-methoxyethanol, methyl acetate, 3-methyl-1-butanol (isoamyl alcohol), methyl butyl ketone, methyl cyclohexane, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, N-methylpyrrolidone, nitromethane, pentane, 1-pentanol, 2-propanol, propyl acetate, pyridine, sulfolane, tetrahydrofuran, tetrahydronaphthalene, toluene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, triethylamine, and xylene. In another embodiment, the solvent or combination of solvents may be water, ethanol, DSMO, DMF, methanol, acetone, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, or toluene. The organic solvents used alone or in combination in step 1 include hexane, p-xylene, toluene, ether, methyl tert-butyl ether (MTBE), diethylamine, dioxane, chlorobenzene, tetrahydrofuran, o-dichlorobenzene (ODCB), ethyl acetate, dimethoxyethane, pyridine, dichloromethane, HMPT, 1,2-dichloroethane, DMPU, acetone, dimethylformamide, tert-butanol, sulfolane, dimethyl sulfoxide, acetonitrile, nitromethane, 2-propanol, benzyl alcohol, ethanol, methanol, ethylene glycol, trifluoroethanol, hexafluoroisopropanol, and water. Water is preferably deionized water or distilled water or deionized distilled water. The non-nutritive sugars and the one or more anthracycline compounds should be dissolved in a solvent or combination of solvents used in the method. Preferred solvents include ethanol, methanol, chloroform, hexane, and their aqueous forms. FDA-approved solvents were listed in June 2017. Q3C – Tables and List Guidance for IndustryProvided in [the relevant source]. FDA-approved solvents may be one or more of the following: acetonitrile, chlorobenzene, cyclohexane, cumene, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, and xylene (within the FDA limits that may be present). Another list of FDA solvents for use in step 1 includes one or more of the following: acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine.

[0036] In some cases, the method for preparing water-soluble complexes may further include a surfactant in the solvent step (step 1) or water step (step 2) of the method described herein. The surfactant may be used in combination with an acid or a base in solution. The surfactant may be a polysorbate surfactant (PSS) and / or a poloxamer surfactant (“PXS”). PXS is a poloxamer surfactant, which is a class of synthetic nonionic amphiphilic triblock linear copolymers consisting of a central hydrophobic chain of a nonpolar poly(propylene oxide) (PPO) block and two hydrophilic chains flanking polar poly(ethylene oxide) (PEO) blocks. Poloxamer surfactants can be obtained with different molecular weights and PPO / PEO ratios. PXS surfactants are commercially available, such as Kolliphor® P (BASF, Florham Park, NJ), Pluronic® (BASF, Florham Park, NJ), Lutrol® (BASF SE, Ludwigshafen, Germany), and Synperonic™ PE (CRODA International PLC, East Yorkshire, UK). PXS surfactants are available in liquid, sheet, and paste physical forms. In one embodiment, PXS is a sheet solid. Polysorbate surfactants (“PSS”) are derived from fatty acid esterified ethoxylated sorbitan and are commercially available, such as 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 example, “20” indicates monolaurate and “80” indicates monooleate. Tween® 80 is also referred to herein as T80, as are other types of Tween®.

[0037] The method may also include drying the water-soluble complex to form a solid. The dried solid can then be redissolved in a suitable liquid.

[0038] In some embodiments, the method for preparing the water-soluble complex may further require the addition of a pharmaceutically acceptable acid in the mixing step of dissolving in the solvent in step 1 and / or in the dissolution in water step 2 after the formation of the complex. The pharmaceutically acceptable acid is present in an amount sufficient to solubilize and homogeneously clarify the reaction mixture. Pharmaceutically acceptable acids used in this method may include 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.

[0039] This method can be used with a surfactant in conjunction with a solvent and anthracycline compounds, or it can be used in the presence of an acid or buffer. The solvent used in this method can be a pure solvent, such as absolute ethanol, or a solvent mixture, such as ethanol, water, and methanol (or other solvents or combinations thereof), as suggested herein. Sugars, pharmaceutical compounds, and solvents can be placed in a container with the surfactant, 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, and even more preferably at least about 24 hours.

[0040] After reading the instructions, these and other implementation schemes will be clear to those skilled in the art, and they provide improvements in patient compliance, satisfaction, comfort, and the overall treatment experience. Brief description of the attached diagram

[0042] Figure 1 The NMR results for a 1:10 molar ratio of doxorubicin hydrochloride to stevioside, prepared by dissolution in ethanol followed by drying and then dissolution in water, are described. Invention Details

[0044] Methods for creating new solubilizing compounds can help pharmacies formulate patient-specific amounts of active compounds and create palatable formulations suitable for pediatric patients. The proposed sugar-drug combination, generated via hydrogen bonding, not only increases the drug's solubility in water but also imparts a sweeter taste, rather than the bitter or pungent taste imparted by excessive salt. Without being bound by theory, the proposed sugar-drug combination is believed to be generated via hydrogen bonding or through host-guest chemistry (e.g., the formation of inclusion compounds or inclusion complexes), where two compounds form a complex and / or one of the chemical compounds forms a cavity that can accommodate a "guest" compound. The interaction between the host and guest in the inclusion complex involves pure van der Waals bonds. In this sugar-compound form, the complex and / or the complex formed from the sugar compound increases the compound's solubility in water relative to the individual compound (not in the complex). The complex also imparts a sweeter taste, rather than the bitter or pungent taste imparted by excessive salt; however, the addition of sugar to form the complex is not as a sweetener but rather to form a complex with anthracycline compounds to improve water solubility in the complex form. A sweeter taste is beneficial when administering medication to young children and elderly patients.

[0045] While complexed non-nutritive sugars and drugs may be more palatable as complexes, it must be understood that the formation of complexes does more than simply mask the taste of the drug. Improved palatability is a secondary benefit. The formation of water-soluble sugar-drug complexes by the methods described herein improves the properties of the drug in complex form, such as improved water solubility. Additionally, improved properties may include improved pharmacokinetic properties, improved stability at pH and / or during storage, and at high temperatures or other conditions. Pharmacokinetic properties include absorption into the system, distribution within the system, metabolism of the complex by the system, and its elimination. Furthermore, based on the data and description herein, it should be understood that water-soluble drug-sugar complexes formed by the methods described herein should not be considered mixtures. The method of dissolving the listed non-nutritive sugars with PSD in the listed solvents or combinations of solvents may optionally be carried out 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 filtered and / or dried. The final complex yields a new, more water-soluble complex form of the drug. The water-soluble sugar-drug complex can then be further mixed with other pharmaceutical excipients, stabilizers, fillers, flavoring agents, sweeteners, etc., as described herein. Only the composition remains in the form of a mixture after the addition of one or more of these other components. The complex formed by the disclosed method involves host-guest chemistry not considered in the formation of such mixtures. The solubility of the complex is independent of the addition of other pharmaceutical excipients, stabilizers, fillers, flavoring agents, sweeteners, etc. The composition of interest may further contain salts such as NaCl, KCl, or citric acid for stabilization purposes, as well as other pharmaceutically acceptable components.

[0046] Another benefit of this method and the products prepared by it is the reduction in the amount of active pharmaceutical ingredient, as greater solubility leads to higher bioavailability. This method offers cost-effectiveness, enabling the preparation of smaller quantities of the active compound using fewer resources while still achieving the desired therapeutic effect in patients.

[0047] The complexation of a drug with DTG or other non-nutritive sugars can be interpreted as a donor (e.g., sugar) and acceptor (e.g., drug) interaction, such as host-guest chemistry between the drug and one or more non-nutritive sugars. In effect, the complexation (chelation) entangles the drug compound with non-nutritive sugars and / or surfactants, which essentially allows the drug to capture the water solubility of the non-nutritive sugars and / or surfactants. See, for example, "Absorption and distribution of steviolglycosides in animal and human models." Stevia TechnologyRetrieved July 31, 2023, from: https: / / www.steviashantanu.com / single-post / 2015 / 11 / 18 / absorption-and-distribution-of-steviol-glycosides-in-animal-and-human-models. Unrestricted by any theory, the enzymatic cleavage of glucose units leads to the depolymerization (e.g., decomplexation) of the sugar-drug complex, releasing the poorly soluble drug. This process is slow enough that most of the amount of drug released at any given time can be absorbed.

[0048] By using powdered or liquid formulations, it is easier to dispense appropriate doses, reducing errors, variability, and waste based on differences in pill-fractionation techniques. Other benefits of this method and the products prepared by it include a reduction in the amount of active pharmaceutical ingredient, as greater solubility leads to higher bioavailability. This method offers cost-effectiveness, utilizing fewer resources to prepare smaller quantities of the active compound while still achieving the desired patient therapeutic effect.

[0049] definition

[0050] The following definitions provide guidance for the interpretation of terms unless the context in which the term appears elsewhere in the specification indicates otherwise.

[0051] As used herein, the terms “optional,” “optional,” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation will occur and the possibility that it will not occur.

[0052] As used herein, the term "about" when used before a numerical indication (such as temperature, time, amount, concentration, etc.) or including a range, indicates a value that can vary (+) or (-) by an approximate value or any subrange and / or between 15%, 10%, 5%, 1%. When referring to dosage use, the term "about" means that the dosage can vary by + / - 10%. When referring to the amount of a modified substance or composition (e.g., kg, L, or equivalent), a value of a physical property, or a parameter value characterizing a process step (e.g., the temperature at which the process step is performed), the term "about" refers to a change in numerical quantity that can occur, for example, through typical measurement, handling, and sampling procedures involved in the preparation, characterization, and / or use of the substance or composition; through unintentional errors in these processes; through differences in the manufacture, source, or purity of the ingredients used to prepare or use the composition or to perform the procedures; and so on. In some embodiments, "about" can refer to a change of ±0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 in appropriate units. In some implementations, “about” can refer to a change of ±1%, 2%, 3%, 4%, 5%, 10%, or 20%.

[0053] As used herein, the terms “comprising” or “including” are intended to mean that a composition or method includes the listed elements, but does not exclude other elements.

[0054] As used herein, the term "substantially composed of" when used to define compositions and methods should mean excluding other elements that have any essential significance for the combination used for the purposes described herein. Therefore, a composition substantially composed of the elements defined herein, or a method substantially composed of the steps defined herein, will not exclude other materials that do not substantially affect the essential and novel features of the claimed subject matter.

[0055] As used herein, the term "composed of" should mean excluding other components or substantial method steps beyond trace elements. The embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0056] The "weight ratio" of "sugar:compound" in the formulation can be any value of 0.1 between about 0.1:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, and 20.0:1.0, and about 0.1:1.0 and about 20.0:1.0.

[0057] The molar ratio of "non-nutritive sugar: pharmaceutical compound" in the formulation can be any value of 0.1 between 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 and about 20:1. Alternatively, the sugar: pharmaceutical compound ratio can be about 1.00:1.00 to about 5.00:1.00, and any value of 0.01 within this range. In one embodiment, a sugar:PSD molar ratio of about 2.0 to about 1.0 is used.

[0058] The use of the terms "sugar" and "non-nutritive sugar" refers to sugars as non-nutritive sweeteners. Non-nutritive sugars are at least 50 times sweeter than glucose and have virtually no calories. One type of non-nutritive sugar is the diterpenoid glycoside "DTG" as used herein. Exemplary DTGs can be stevia glycoside, durcuric acid B (also known as riboflavin C), stevia, riboflavin A (also known as steviol glycoside A3), and steviol glycoside (a diterpenoid glycoside with the chemical formula C). 38 H 60 O 18 ), n-octyl glucose, n-lauryl-β-D-maltodextrin (also known as dodecyl maltodextrin or lauryl maltodextrin), stevia (chemical formula C 44 H 70 O 23 ), steviol glycosides, for example, are derived from Stevia rebaudiana It can also be any other sugar discussed herein. While other stevia-like sugars are known, only those approved by the FDA GRAS are used in water-soluble sugar-drug complexes administered to human subjects. Preferably, the sugar is one or more of stevia, stevia, durcuric acid B, steviol, n-lauryl-β-D-maltose, or ribobadiol A, which can be used in any combination or arrangement. Any arrangement of these six listed sugars (two of the sugars, three of the sugars, etc.) has also been used. The price of the sugar may be a factor in whether it is a commercially viable sugar for dissolving poorly soluble or soluble drug compounds. Exemplary sugars used to prepare the “water-soluble sugar-drug complex” include stevia, durcuric acid A, durcuric acid B, sucrose, D-fructose, sucralose, ribobadiol A, ribobadiol B, ribobadiol D, steviol, stevia n-octylglucose, or n-lauryl-β-D-maltose.

[0059] Unbound by theory, it is believed that when non-nutritive sugars, as discussed herein, are compounded with pharmaceutical compounds, stable complexes are formed, presumably through non-covalent hydrogen bonds and optional hydrophobic-hydrophobic interactions, such as van der Waals forces. “Sugar” or “non-nutritive sugar” as used herein can be durcuric acid A, sucrose, D-fructose, sucralose, ribobadiol B, ribobadiol D, stevia, n-octylglucose, advantamé®, neotame®, sematrandezidine, saccharin, monk fruit, aspartame, acetylsupanose (Ace-K), allulose, stevia glycosides, durcuric acid B (also known as ribobadiol C), ribobadiol A (also known as stevioside A3), stevioside (diterpenoid disaccharide glycoside), n-octylglucose, and stevioside, for example, derived from… Stevia rebaudiana Those.

[0060] ADVANTAME® is an aspartame analog; N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-aspartic acid]-L-phenylalanine-1-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 insulin spikes.

[0061] NEOTAME® – trade name NEOTAME® – is an aspartame derivative, classified as an aspartic acid-derived dipeptide. NEOTAME® has a low glycemic index (GI) and zero calories, but can cause insulin spikes.

[0062] Soma sweet – also known as TALIN®, is a mixture of soma sweet I and soma sweet II, sweet proteins derived from Thaumatococcus danielli.

[0063] Saccharin – also known as saccharin or benzosulfonamide, in salt forms such as sodium saccharin and calcium saccharin. 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 insulin spikes.

[0064] Sucralose – sold under the name Splenda – is an organochlorine sweetener with the chemical name 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4-deoxy-α-D-galactopyranoside (Schiffman et al., “Sucralose, ASynthetic 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.

[0065] Monk fruit – also known as Siraitia grosvenorri, swingle fruit, monk fruit, and andluohan guo – is from which a calorie-free sweetener is obtained. The FDA designates it as Swingle Fruit Extract (SGFE). The compounds that produce the sweetness are mogrosides, which have a mogrol backbone and glucose units (glycosides) linked to it. They are sold under the trademark Monk Fruit in Raw®, Lakanto®, PureLo®, Splenda® Monk Fruit Sweetener, SweetLeaf®, and Whole Earth®. SGFE is shown not to raise blood sugar levels.

[0066] Aspartame – sold under the names Nutrasweet, Equal, and Sugar Twin – is calorie-free. Its chemical name is L-aspartic-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 insulin spikes.

[0067] Acetylsuppan potassium – also known as Ace-K, 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.

[0068] Allulose is a sugar naturally found in figs and raisins. Also known as D-psicose or D-allulose, it has very few calories. It does not affect insulin or blood glucose levels. (Tani et al., “Allulose for theattenuation of postprandial blood glucose levels in healthy humans: A systematic review and meta-analysis,” PLoS One 18(4): e0281150, 2023.)

[0069] The sweetness of non-nutritive sugars is compared to that of table sugar (sucrose), as summarized in the table below obtained from the US FDA:

[0070] "Stable" water-soluble complexes may include hydrogen-bonded non-nutritive sugars and compounds that can be prepared and isolated, and whose structure and properties remain or can be made substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject). The pharmaceutical compound of a stable water-soluble complex is an anthracycline compound or a pharmaceutically acceptable salt, hydrate, cocrystal, polymorph, or solvate of an anthracycline compound. An exemplary anthracycline compound is doxorubicin or a pharmaceutically acceptable salt thereof in a formulation containing one of the sugars produced by the disclosed methods.

[0071] This method involves dissolving anthracycline compounds in a solvent in the presence of non-nutritive sugars and / or surfactants, followed by drying the solvent in the composition. The dried composition is dissolved in water to determine its water solubility, and optionally further dried and / or filtered. The resulting water-soluble complex can then be formulated into a solid form for oral administration, such as pills, capsules, capsule-shaped tablets, chewable tablets, tablets, lozenges, and soft gels. The water-soluble complex can also be formulated into suppositories, lotions, gels, or ointments. The water-soluble complex can be formulated into a suitable topical form. Alternatively, the water-soluble complex can be formulated into an injectable liquid for subcutaneous (SC), intravenous (IV), intraperitoneal (IP), and intramuscular (IM) injection into subjects. Alternatively, the water-soluble complex can be formulated into a liquid formulation for administration. In the case of non-human subjects, the lyophilized water-soluble complex can be administered to non-human subjects as a powder or liquid formulation. Additionally, the lyophilized water-soluble complex can be formulated as a food additive or animal feed additive.

[0072] As used herein and in this provisional application, a "sugar-compound" or "hydrogen-bonded sugar-compound" is a water-soluble complex formed using the disclosed methods. Other water-soluble complexes also include pharmaceutical compounds and surfactants, as well as those that are pharmaceutical compounds, surfactants, and non-nutritive sugars.

[0073] The method described herein for preparing a water-soluble complex comprising anthracycline compounds involves dissolving the pharmaceutical compound in one or more solvents (e.g., ethanol) in the presence of specified non-nutritive sugars and / or surfactants, and then drying or evaporating the liquid from the composition (e.g., freeze-drying, lyophilization, or other methods of evaporating one or more solvents from the mixture). Evaporation can be performed using various steps, including pre-freezing of the complex followed by primary and secondary drying steps. If lyophilization is used, conventional lyophilization auxiliaries can be used in combination with the complex in solution. The dried complex is then dissolved in water, and the water can optionally be filtered or dried under high vacuum. The water-soluble complex in water can be dried again to formulate a mixture with other components.

[0074] In another embodiment, the solvent or combination of solvents 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 distilled water. The solvent may also be one or more of acetonitrile, chlorobenzene, cyclohexane, cumene, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, and xylene, within the permissible FDA restrictions. Another list of FDA-approved solvents for use in step 1 includes one or more of the following: acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine.

[0075] The water-soluble complexes formed by the methods described herein can optionally be formulated into solid forms for oral, sublingual, and / or sublingual administration, such as pills, capsules, capsule-shaped tablets, chewables (e.g., gels), tablets, lozenges, and / or soft gels. Water-soluble drug complexes (hydrogen-bonded and / or encapsulated complexed sugar-drug compounds) can also be formulated into inhalable powders. Alternatively, water-soluble complexes can be formulated into injectable liquids for subcutaneous (SC), intravenous (IV), intraperitoneal (IP), and intramuscular (IM) injection into subjects. Such formulations can be used for cosmetic or therapeutic purposes. Alternatively, lyophilized water-soluble complexes can be formulated into liquid formulations for administration, such as for metered nasal sprays, inhalation mists, eye drops, or nebulization by a patient. In the case of non-human subjects, lyophilized water-soluble complexes can be administered to non-human subjects as powders or liquid formulations. Additionally or alternatively, lyophilized water-soluble complexes can be formulated as food additives or additives in animal feed. The PSD must be a PSD that is completely or partially soluble in aqueous solutions of 95% ethanol, 50% or higher ethanol (e.g., 50%, 55%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94% and 95% spectrophotometric grade ethanol) in the presence of non-nutritive sugars. Preferably, the PSD, sugar, and optionally pharmaceutically acceptable acid are soluble in at least about 85% ethanol. Optionally, the water-soluble complex remains soluble without forming a precipitate for at least 24 hours after formation.

[0076] If desired, polyethylene glycol (PEG) may optionally be added to liquid and powder formulations to further improve bioavailability and stability. Typically, PEG is used in quantities between 2000 and 6000 Daltons, 3000 and 4500 Daltons, or 3200 and 3700 Daltons, as well as other pharmaceutically acceptable molecular weights used when formulating PEG with chemical compounds. Commonly used commercially available PEG forms have molecular weights of 3350, 4000, and 6000 Daltons. PEG can be prepared, for example, in a polydisperse or monodisperse manner. If polydisperse, the molecular weight describes the weight-average molecular weight of the preparation. Depending on whether the formulation is in powder or liquid form, the weight ratio of PEG to the anthracycline compound can be between 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1, and includes these values. In one embodiment, the weight ratio is about 8:1. However, the addition of PEG forms a mixture with the water-soluble complex, and PEG itself is not part of the complex.

[0077] For administration, the powder form can be reconstituted at the time of manufacture, at the dispensing pharmacy, or by the patient in a liquid solvent. The liquid solvent can be water, a buffered aqueous solution, syrup, or an aqueous beverage, such as an energy drink or an electrolyte-rich beverage. For example, the water-soluble complex can be reconstituted in sterile saline or other sterile liquid carriers for administration to the subject as eye drops or via subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravenous (iv), oral (orally into the gastrointestinal tract or for oral or sublingual administration), or local (e.g., skin application). The water-soluble complex can also be formulated as a dose-controlled nasal spray or delivered via subcutaneous or intramuscular injection.

[0078] Ingredients suitable for formulating tablets, pills, or other solid oral forms of the water-soluble complex may include, for example, any one or all of corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, and hydroxypropyl methylcellulose. Other compositions incorporated into the water-soluble complex may include shaping agents, oral stool softeners, oral stimulants, and / or rectal suppositories.

[0079] While the dissolution of water-soluble complexes is slow enough to allow the drug to move into the small intestine without precipitating in the stomach, other methods for prolonging drug release are known, such as enteric-coated tablets, coating the complex with a slow-dissolving polymer (where the polymer can be selected by the desired length and / or thickness, which can alter the drug release rate), encapsulating the complex in gel capsules, placing the complex in an insoluble matrix (e.g., Slow-K or Imdur Durules), placing the complex in an aggressive matrix (e.g., MST Continus, Phyllocontin Continus), and / or encapsulating the complex in a semi-permeable membrane. See, for example, “Pharmaceutical Issues when Crushing, Opening or Splitting Oral Dosage Forms,” Royal Pharmaceutical Society, June 2011. Other modulated-release oral dosage forms include “extended-release drug products,” where the dosage form of the complex allows for at least a two-fold reduction in dosing frequency compared to drug complexes without extended-release forms. Examples of extended-release dosage forms include controlled-release, sustained-release, and / or long-acting drug products. Other modulated-release oral doses are delayed-release drug products. In delayed-release forms, the dosage form of a water-soluble complex releases one or more discrete portions of the drug at a given time after administration, rather than immediately. Enteric-coated dosage forms are common delayed-release products (e.g., enteric-coated aspirin and other NSAID products). Another modulated-release oral form of a water-soluble complex used is a targeted-release drug product. This is a dosage form that releases the drug from the water-soluble complex at and / or near the intended physiological site of action. Another modulated-release oral dose of a water-soluble complex is an orally disintegrating tablet (ODT) or equivalent. ODTs have been developed to rapidly disintegrate in saliva after oral administration. Water-soluble complexes in ODT form can be used without the addition of water. The water-soluble complex is dispersed in saliva and is swallowed with little or no water.

[0080] For veterinary use, the formulation can be administered, for example, in animal feed or chewable form. Anthracyclines are a class of drugs commonly used alone or in combination with other agents, surgery, heat therapy, and / or radiation for cancer chemotherapy. Currently, anthracyclines are being used to treat a variety of cancers, including leukemia, lymphoma, breast cancer, stomach cancer, uterine cancer, ovarian cancer, bladder cancer, and lung cancer. Some of the more important anthracyclines include doxorubicin, daunorubicin (also known as acetyldaunorubicin and leukaemomycin C), epirubicin, and edabicin.

[0081] For example, doxorubicin is used to treat cancers in animals, such as lymphoma, osteosarcoma, other sarcomas, carcinomas, and melanomas, especially in small animals. It often causes allergic reactions in patients, which can be prevented by pretreatment with the antihistamine diphenhydramine. In humans, doxorubicin (also known as hydroxydanomycin hydrochloride and hydroxydoxorubicin hydrochloride) is used to treat certain types of bladder cancer, breast cancer, lung cancer, stomach cancer, and ovarian cancer; Hodgkin lymphoma (Hodgkin's disease) and non-Hodgkin lymphoma (cancers that begin in the cells of the immune system); and certain types of leukemia (cancers of white blood cells), including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML, ANLL). Doxorubicin is also used alone or in combination with other drugs to treat certain types of thyroid cancer and certain types of soft tissue or osteosarcoma (cancers that form in muscles and bones). It is also used to treat neuroblastoma (a cancer that begins in nerve cells and mainly occurs in children) and Wilms' tumor (a type of kidney cancer that occurs in children). For indications used as part of an FDA-approved monotherapy or combination therapy, or for other indications not approved by the FDA, please refer to the StatPearls [Internet] entry for anthracyclines available at ncbi.nlm.nih.gov / books / NBK538187 / , last updated January 30, 2023. Doxorubicin has a solubility of approximately 2% in water. Daunorubicin is considered to be soluble up to 50 mM in water and soluble in some aqueous alcohols. Epirubicin hydrochloride has a solubility of up to 50 mM in water and up to 100 mM in DMSO (dimethyl sulfoxide), but its solubility in aqueous buffers is very low. Idarubicin hydrochloride has a water solubility of approximately 0.772 mg / mL. A list of anthracyclines to consider in combination with single non-nutritive sugars, surfactants, or surfactants and non-nutritive sugars is provided below:

[0082] Ingredients suitable for formulating tablets, pills, or other solid oral forms of water-soluble complexes may include, for example, any one or all of corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, and hydroxypropyl methylcellulose. Other compositions incorporated into the water-soluble complex may include shaping agents, oral stool softeners, oral stimulants, and / or rectal suppositories.

[0083] The terms "patient" and "subject" include animal patients or animal subjects. Patients and subjects who can be treated with the compositions disclosed herein can be human or veterinary. Commonly infected veterinary animals include horses, alpacas, dogs, cats, poultry (e.g., ducks, geese, and chickens), cattle, pigs, agricultural ruminants, and various zoo animals.

[0084] Any component may be packaged in a kit, individually in a separate container, or as a mixture of each other. The end user may reconstitute the components with the included diluent or a diluent of her choice. In addition to the components, individually or in a mixture, the kit may include instructions for use, mixing and / or application tools, storage containers, etc.

[0085] The terms “compound,” “pharmaceutical compound,” and “drug” mean anthracycline compounds or their pharmaceutically acceptable salts, solvates, cocrystals, polymorphs, hydrates, or solvates that can be used as a drug in a subject (animal or human). Drugs and chemicals used include those that are insoluble in water and those that are soluble in water. A compound or drug can be any salt, hydrate, polymorph, or salt in free form of said compound or drug. The drug or compound must be those that are completely or partially soluble in 95% ethanol, 50% or higher (50%, 55%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, and 95% spectrophotometric grade ethanol) in the presence of sugars. The dissolved sugars, anthracycline compounds, and / or the solvent from step 1 are dried. Step 2 involves dissolving the dried composition in water (Step 2). After dissolution in water, the stability of the water-soluble complex in the solution can be evaluated for up to 24 hours. FDA-approved anthracyclines include daunorubicin, doxorubicin, epirubicin, edabicin, mitoxantrone, and penoxorubicin (which indicates that they may be in free form, salt form, or other forms of the drug as indicated).

[0086] The term "pharmaceutically acceptable salt" refers to a salt (including internal salts such as zwitterions) that has similar efficacy to a pharmaceutical compound and is not biologically or otherwise undesirable (e.g., non-toxic and harmless to its recipient), preferably approved by the U.S. FDA or the European Medicines Agency (EMA). Therefore, one embodiment of the invention provides a pharmaceutically acceptable salt of the compounds of the invention. As used herein, the term "salt" means any of the following: an acid salt formed with an inorganic and / or organic acid, and a base salt formed with an inorganic and / or organic base.

[0087] Pharmaceutically acceptable acids used in the methods described herein include 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-ketoglutaric acid; 4-acetaminobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); decanoic acid; hexanoic acid; caprylic acid; carbonic acid; cinnamic acid; citric acid; cyclohexane; dodecyl sulfate; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactopyric acid; Gentianic acid; glucoheponic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutamate; glycerophosphate; 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; dihydroxynaphthyl acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanate; toluenesulfonic acid ( p ); and undecenoic acid. See, for example, edited by PH Stahl and CG Wermuth. Handbook of Pharmaceutical Salts Weinheim / Zürich: Wiley-VCH / VHCA , 2002.

[0088] "Pharmaceutically acceptable composition" refers to a composition comprising a water-soluble complex and one or more carriers, excipients (e.g., gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, and PEG), stabilizers (e.g., glycine, vitamin E, carboxymethyl cellulose, sodium lauryl sulfate), thickeners, and further sweeteners. Compositions comprising the water-soluble complex may be in solid or liquid form.

[0089] The "salt" used to mix with the formed water-soluble complex refers to the presence of KCl and HCl to form the mixture, rather than to aid dissolution in any step. Salts include sodium chloride (NaCl) and potassium chloride (KCl). Salts are added in an amount sufficient to enhance the absorption of water-soluble drugs by the subject. Sodium and potassium play a crucial role in the body's hydration process by acting as magnets to draw water into cells, a key factor in maintaining proper hydration. This mechanism ensures that water moves more efficiently into and out of cells to support basic bodily functions.

[0090] The “improved solubility” of a drug refers to the improvement in the solubility of the drug in water in its complex form, measured at 20°C, relative to its solubility when not complexed with a sugar, wherein the sugar-drug complex is formed by the methods described herein. The solvent used to dissolve the compound and non-nutritive sugar can be 80% methanol, 95% (ACS grade), absolute methanol or higher, and combinations of methanol and ethanol, or methanol and water, or other solvents listed herein. Combinations or combinations containing hexane may also be used. In another embodiment, the solvent or solvent combination can be water, ethanol, DSMO, DMF, methanol, acetone, chloroform, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, or toluene. After dissolving the sugar and compound in ethanol or aqueous ethanol, the ethanol (or other solvent) is evaporated, for example, under a high rotating vacuum. The dissolved sugar and compound can be dissolved in any of the said solvents and then dried as described herein. The powder obtained from the evaporation step can then be redissolved (dissolved) in water. As described above, the improvement in the water solubility of the compound, now in its complex form, is measured at approximately 20°C.

[0091] "Daily unit dose" refers to the total amount of the drug compound administered to the subject per day, whether administered once or multiple times, and when administered once, whether using one formulation or multiple formulations. The dose of a formulation containing the drug compound (e.g., as a water-soluble complex) will contain any formulation component, such as non-nutritive sugars and / or surfactants, in amounts not exceeding the Generally Recognized As Safe (GRAS) level. For example, when using steviol sugar as a non-nutritive sugar, the dose will provide no more than about 10 mg / kg of steviol sugar, as exceeding this dose would result in a single dose of 700 mg of sugar for an average 70 kg male. In another embodiment, the dose will provide the subject with no more than 5.0 mg / kg of steviol sugar. Amounts of 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, and 6.0 mg / kg of steviol sugar per dose are also used.

[0092] The term "treatment" refers to treatment of a subject who requires anthracyclines, which are frequently used to treat cancer. Subjects can be humans, dogs, cats, or other animals.

[0093] The terms “poorly water-soluble drug,” “PSD,” and “drug compound” refer to a drug approved by a regulatory agency whose water solubility in distilled water, when used alone, does not exceed 10 mg / mL. Regulatory-approved drugs can be those approved by the U.S. FDA, the U.S. Department of Agriculture (USDA), and / or the EMA.

[0094] The term "sugar-compound" refers to a hydrogen-bonded composition in which a non-nutritive sugar binds to a pharmaceutical compound via novel hydrogen bonds to form a water-soluble complex, wherein the compound is an anthracycline or a pharmaceutically acceptable salt of an anthracycline. The water-soluble complex also includes surfactants and pharmaceutical compounds, as well as surfactants, pharmaceutical compounds, and non-nutritive sugars.

[0095] "Pharmaceutically acceptable composition" refers to a composition comprising a water-soluble complex and one or more carriers, excipients (e.g., gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, and PEG), stabilizers (e.g., glycine, vitamin E, carboxymethyl cellulose, sodium lauryl sulfate), thickeners, and further sweeteners. The composition may be solid or liquid.

[0096] When measured in water at 20°C, the "improved solubility" of a compound in the form of a water-soluble complex is compared to that of a compound that is not a complex.

[0097] The term "sugar" is used to refer to sugars that are non-nutritive sweeteners. Non-nutritive sugars used in this article may include stevioside, durcuric acid A, durcuric acid B (also known as retinoside C), sucrose, stevia, D-fructose, sucralose, retinoside A (also known as steviol glycoside A3), retinoside B, retinoside D, and steviol glycosides (also known as diterpenoid glycosides with the chemical formula C). 38 H 60 O 18 ), n-octyl glucose, n-lauryl-β-D-maltodextrin (also known as dodecyl maltodextrin or lauryl maltodextrin), stevia (chemical formula C 44 H 70 O 23 ), steviol glycosides, for example, derived from Stevia rebaudiana And n-octyl glucose, as well as other non-nutritive sweeteners discussed herein. Other steviol glycosides and non-nutritive sweeteners used for hydrogen bonding with drugs / compounds include ribobadiol E, ribobadiol F, and steviolbioside.

[0098] One method for improving the solubility of a compound includes taking the compound and dissolving it in about 70% to 95% ethanol (or a combination of other solvents) in the presence of a sugar. The compound:sugar weight ratio can be about 0.1:1.0 to about 1.0:1.0, about 1.0:1.0 to about 1.0:10.0 or 1.0:20.0, and any 0.1 value between about 0.1 and about 20.0. More preferably, the drug:sugar molar weight ratio is about 1:10 or 1:5, or any 0.1 value less than 5.0, such as 1.4, 0.7, and 0.1.

[0099] Another feature imparted by the method of forming the water-soluble complex is that it can improve the storage stability of the compound.

[0100] The foregoing disclosure generally describes the present invention. A more complete understanding can be obtained by referring to the following specific embodiments, which are provided herein for illustrative purposes only and are not intended to limit the scope of the invention. The amounts of non-nutritive sugars used in the embodiments are also claimable amounts and should not be excluded from the claims simply because such amounts are referenced in the embodiments.

[0101] Example

[0102] In all the following examples, the same conditions were used unless otherwise stated. The water used was deionized water. 95% ethanol (ACS spectrophotometric grade, unless otherwise stated) was used. In all cases, high-vacuum drying was performed at room temperature. All examples used an Edvards Model RV8 high-vacuum pump equipped with an IKA C-mag HS7 magnetic stirrer. The rotary evaporator used was a Heidolph Basis Hei-VAP value (No. 560-00000-01-1).

[0103]

[0104] Example 1—Doxorubicin Hydrochloride and Stevioside

[0105] Typically, the components are deposited into a sealed container containing ethanol and vortexed to form a clear solution containing small particles. The solution is centrifuged as part of step 1. The ethanol is evaporated, and the dried mixture is dissolved in water (step 2), producing a clear, homogeneous red mixture. The mixture is centrifuged again, and the supernatant is filtered through a membrane. The flow-through is dried to form the doxorubicin hydrochloride-stevioside complex. Alternatively, the solvent in the mixture can be dried under high vacuum without using a centrifuge.

[0106] In this embodiment, a single-necked RB flask dried in an oven equipped with a magnetic stir bar was used. Doxorubicin hydrochloride (5.0 mg; 0.082 mmol) and steviol glycoside (69.4 mg; 0.062 mmol) in a molar ratio of 1:10 were weighed and added to the RB flask, followed by 2.0 mL of absolute ethanol (spectrophotometric grade, 95%).

[0107] The reaction mixture was vigorously stirred at 20°C at room temperature to produce a clear solution with only small particles remaining and a pH of approximately 4.8 (Step 1). Ethanol was removed from the mixture by vacuum drying at a bath temperature of 35°C using an Edvards Model # RV8 magnetic stirrer, an IKA Model C-MAG HS7 rotary evaporator, Heidolphtype Basis Hei-VAP Value, No. 560-00000-0101, at room temperature and with a high vacuum pump to completely remove ethanol (EtOH). The high vacuum pump was connected to a cooling trap, which was connected to an RB flask. The vacuum level was approximately 1 mm Hg.

[0108] Step 2: The dried solid containing steviol glycoside and doxorubicin hydrochloride was then dissolved in 2.0 mL of deionized water at room temperature with stirring to obtain a clear, homogeneous red solution. NMR analysis of the water-soluble composition showed that a water-soluble complex had formed between steviol glycoside and doxorubicin hydrochloride, with doxorubicin hydrochloride achieving a solubility close to 100%. See also Figure 1 .

[0109] Water can be removed from the mixture at 35°C using a rotary evaporator and a high-vacuum pump. The solid can be further dried, for example, for an additional hour under high-vacuum conditions at room temperature, to completely remove water (confirmed by changes in weight loss). Continue drying until no further weight loss is observed.

[0110] Implementation Plan

[0111] This includes the following implementation schemes and various combinations.

[0112] Implementation Scheme [1] A method for improving the solubility of a compound, comprising: a) mixing the compound with a sugar in a solvent, wherein the compound is an anthracycline compound or a pharmaceutically acceptable salt thereof; and b) removing the solvent to obtain a powder.

[0113] Implementation scheme [2]. The method of implementation scheme [1], wherein the compound and sugar are present in a weight ratio of about 0.1:1.0 to about 1.0:10.0.

[0114] Implementation scheme [3]. The method of implementation scheme [2], wherein the compound and sugar are present in a weight ratio of 1.0:1:10.0.

[0115] Implementation scheme [4]. The method of any one of Implementation Schemes [1] to [3], wherein the sugar is stevia glycoside, durcuria glycoside A, durcuria glycoside B, sucrose, D-fructose, sucralose, riboboroside A, riboboroside B, riboboroside D, stevioside, stevia, n-octyl glucose, n-lauryl-β-D-maltodextrin, ADVANTAME®, NEOTAME®, semathymidine, saccharin, sucralose, stevioside, monk fruit, aspartame, acetylsupanose, or allulose.

[0116] Implementation scheme [5]. The method of any one of implementation schemes [1] to [4], wherein the solvent is ethanol, water, ethanol or a pharmaceutically acceptable solvent.

[0117] Implementation scheme [6]. The method of any one of implementation schemes [1] to [5], wherein the solvent is ethanol, and is about 70% to about 95% ethanol.

[0118] Implementation scheme [7]. The method of any one of implementation schemes [1] to [6], wherein the solvent is 95% ethanol.

[0119] Implementation scheme [8]. The method of any one of implementation schemes [1] to [7] further includes dissolving the obtained powder in a second solvent and optionally filtering the dissolved powder.

[0120] Implementation Scheme [9]. A powdered formulation of a compound obtained by any one of the methods of Implementation Schemes [1] to [8], wherein the compound has improved solubility through hydrogen bonding between the compound and sugar.

[0121] Implementation scheme

[10] . A powdered formulation of the compound of implementation scheme [9], wherein the weight ratio of the compound to sugar is about 0.1:1.0 to about 1:10.0.

[0122] Implementation scheme

[11] . The powdered formulation of implementation scheme

[10] wherein the weight ratio of the compound to the sugar is about 1.0 to about 10.0.

[0123] Implementation scheme

[12] . A powdered formulation of any one of implementation schemes [9] to

[11] , wherein the anthracycline compound or a pharmaceutically acceptable salt thereof is daunorubicin, doxorubicin, epirubicin, edabicin, mitoxantrone, penoxorubicin, aldoxorubicin, anamycin, procainoxicin, pirarubicin, arubicin or a pharmaceutically acceptable salt thereof.

[0124] Implementation scheme

[13] . A powdered formulation of any one of implementation schemes [9] to

[12] , wherein the powdered formulation is adapted to be reconstituted in water or salt water, and wherein, when reconstituted in water or salt water, the compound in the sugar-bonded formulation has higher solubility than the compound in the absence of sugar bound to the compound.

[0125] Implementation Scheme

[14] . A powdered formulation of any one of Implementation Schemes [9] to

[13] , wherein the sugar is stevia, durcuria glycoside A, durcuria glycoside B, sucrose, D-fructose, sucralose, riboboroside A, riboboroside B, riboboroside D, stevia, stevia, n-octyl glucose, n-lauryl-β-D-maltodextrin, ADVANTAME® ([N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-[α]-aspartic acid]-L-phenylalanine 1-methyl ester monohydrate]), NEOTAME® ([N-(3,3-dimethylbutyl)-L-α-aspartic acid-L-phenylalanine 2-methyl ester]), somatase ([N-[4-(4-cycloheptylpiperazin-1-yl)sulfonylphenyl]acetamide]), saccharin ( [1,1-dioxo-1,2-benzothiazol-3-one]), sucralose [sucralose or Splenda®], stevioside, monk fruit, aspartame, acetylsupan potassium (Ace-K or 6-methyl-2,2-dioxo-1-oxa-2λ6-thia-3-azacyclohexane-5-en-4-one) or allulose [(3R,4R,5R)-2-(hydroxymethyl)oxacyclohexane-2,3,4,5-tetraol].

[0126] Implementation scheme

[15] . A powdered formulation of any one of implementation schemes [9] to

[15] , wherein the anthracycline compound is doxorubicin or a pharmaceutically acceptable salt thereof.

[0127] Implementation scheme

[16] . The powdered formulation of implementation scheme

[15] , wherein the anthracycline compound is doxorubicin hydrochloride.

[0128] Implementation scheme

[17] . A powdered preparation of any one of implementation schemes [9] to

[16] , which is used to prepare feed, tablets, capsules, capsule-shaped tablets, suppositories or food additives.

[0129] Implementation scheme

[18] . A liquid formulation of a compound, wherein the powder formulation of any one of the implementation schemes [9] to

[16] is dissolved in a liquid, syrup, gel or beverage.

[0130] Implementation scheme

[19] . Liquid formulation of implementation scheme

[18] , wherein the liquid is water or saline and optionally sterile.

[0131] Implementation Scheme

[20] . A kit for preparing a liquid formulation of a powdered formulation of any one of embodiments [9] to

[17] , comprising the powdered formulation and a sterile liquid, and optionally comprising instructions for mixing the powdered formulation and the sterile liquid to prepare the liquid formulation.

[0132] Implementation Scheme [1A]. A method for preparing a water-soluble complex, comprising: a) mixing a compound with a non-nutritive sugar in one or more solvents, wherein the compound is an anthracycline compound or a pharmaceutically acceptable salt, solvate, eutectic, hydrate or polymorph thereof; b) removing the solvent to obtain a powder composition; c) dissolving the powder composition in water, optionally dissolving it in water together with an acid to obtain a water-soluble complex, optionally filtering the water-soluble complex; and wherein the compound in the water-soluble complex has improved solubility compared to the solubility of compounds not in the water-soluble complex.

[0133] Implementation scheme [2A]. The method of implementation scheme [1A] further includes drying the water in the water-soluble complex.

[0134] Implementation scheme [3A]. The method of implementation scheme [1A], wherein the compound and the non-nutritive sugar are present in a molar ratio of about 0.1:1.0 to about 1.0:20.0.

[0135] Implementation scheme [4A]. The method of implementation scheme [1A] further includes a nonionic surfactant in step a to form a water-soluble complex containing a nonionic surfactant, a non-nutritive sugar and a compound.

[0136] Implementation scheme [5A]. The method of implementation scheme [4A], wherein the nonionic surfactant is a polysorbate surfactant or a poloxamer surfactant, and wherein the molar ratio of the compound to the nonionic surfactant is from about 1:0.5 to about 1:5.0.

[0137] Implementation scheme [6A]. The method of implementation scheme [2A], wherein the compound and the non-nutritive sugar are present in a molar ratio of about 1.0:10.0.

[0138] Implementation scheme [7A]. The method of any one of implementation schemes [1A] to [6A], wherein the non-nutritive sugar is stevia glycoside, durcuric acid A, durcuric acid B, sucrose, D-fructose, sucralose, riboboroside A, riboboroside B, riboboroside D, stevioside, stevia, n-octyl glucose, n-lauryl-β-D-maltodextrin, ADVANTAME®, NEOTAME®, semathymidine, saccharin, sucralose, stevioside, monk fruit, aspartame, acetylsupanose, or allulose.

[0139] Implementation scheme [8A]. The method of any one of implementation schemes [1A] to [6A], wherein the solvent is ethanol, water, methanol or a combination thereof.

[0140] Implementation scheme [9A]. The method of any one of implementation schemes [1A] to [6A], wherein the solvent is ethanol, and is about 70% to about 95% ethanol.

[0141] Implementation scheme [10A]. The method of implementation scheme [8A], wherein the solvent is 95% ethanol.

[0142] Implementation scheme [11A]. The method of any one of implementation schemes [1A] to [10A] further includes drying the water-soluble complex dissolved in water.

[0143] Implementation scheme [12A]. The method of implementation scheme [1A], wherein step a) and / or step b) further includes adding a pharmaceutically acceptable acid to a solvent or water.

[0144] [Implementation Scheme 13A]. The method of Implementation Scheme [12A], wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutamate, 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.

[0145] Implementation scheme [14A]. The method of any one of implementation schemes [1A] to [13A], wherein the anthracycline compound or its pharmaceutically acceptable salt, solvate, hydrate, cocrystal or polymorph is daunorubicin, doxorubicin, epirubicin, edabacin, mitoxantrone, pentorubicin, aldoxorubicin, anamycin, purcamycin, pirarubicin or arubicin.

[0146] Implementation scheme [15A]. A water-soluble complex prepared by any one of implementation schemes [1A] to [14A].

[0147] Implementation scheme [16A]. The water-soluble complex of implementation scheme [15A], wherein the water-soluble complex is stable in water at a pH of about 8.5 and / or a pH of 4.0 for at least two hours.

[0148] Implementation Scheme [17A]. A pharmaceutically acceptable composition comprising a water-soluble complex of any one of Implementation Schemes [15A] or [16A], wherein, when measured at 20°C, the compounds in the water-soluble complex have at least a 50% improvement in water solubility compared to the individual compounds.

[0149] Implementation scheme [18A]. Pharmaceutically acceptable composition of implementation scheme [17A], wherein the non-nutritive sugar is present in a daily unit dose not exceeding 280 mg.

[0150] Implementation scheme [19A]. A pharmaceutically acceptable composition of implementation scheme [17A], wherein the compound is in a weight ratio of about 0.1:1.0 to about 1:10.0 to a non-nutritive sugar.

[0151] Implementation scheme [20A]. A pharmaceutically acceptable composition of implementation scheme [17A], wherein the compound is in a weight ratio of about 1.0 to about 10.0 to a non-nutritive sugar.

[0152] Implementation Scheme [21A]. A pharmaceutically acceptable composition of any one of Implementation Schemes [17A] to [20A], wherein the anthracycline compound or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal or polymorph thereof is daunorubicin, doxorubicin, epirubicin, edabacin, mitoxantrone, pentorubicin, aldoxorubicin, anamycin, purcamycin, pirarubicin, arubicin, and optionally further comprises citric acid, HCl or KCl.

[0153] Implementation Scheme [22A]. A pharmaceutically acceptable composition of any one of Implementation Schemes [17A] to [20A], wherein the nonnutritive sugar is one or more of stevia glycoside, durcuric acid A, durcuric acid B, sucrose, D-fructose, sucralose, riboboroside A, riboboroside B, riboboroside D, stevioside, stevia, n-octyl glucose, n-lauryl-β-D-maltodextrin, ADVANTAME®, NEOTAME®, semathymidine, saccharin, sucralose, stevioside, monk fruit, aspartame, acetylsupanose, or allulose.

[0154] Implementation scheme [23A]. Pharmaceutically acceptable composition of implementation scheme [21A], wherein the anthracycline compound is doxorubicin or a pharmaceutically acceptable salt, solvate, hydrate, eutectic or polymorph thereof.

[0155] Implementation scheme [24A]. Pharmaceutically acceptable composition of implementation scheme [23A], wherein the anthracycline salt is doxorubicin hydrochloride.

[0156] Implementation scheme [25A]. A pharmaceutically acceptable composition of any one of implementation schemes [17A] to [20A], used in the preparation of feed, tablets, capsules, capsule-shaped tablets, suppositories or food additives.

[0157] Implementation Scheme [26A]. A kit for preparing a liquid formulation of a water-soluble complex comprising a water-soluble complex of any one of Implementation Schemes [15A] or [16A] and a sterile liquid, and optionally instructions for mixing the powdered formulation and the sterile liquid to prepare the liquid formulation.

[0158] Implementation Scheme [27A]. A method of treating a cancer patient, the method comprising administering to the patient in an amount sufficient to inhibit cancer progression a water-soluble complex of any one of implementation schemes [15A] or [16A] or a pharmaceutically acceptable composition of any one of implementation schemes [17A] to [25A].

[0159] Implementation scheme [28A]. Use of the water-soluble complex of any one of implementation schemes [15A] or [16A] in the preparation of a medicament for treating cancer.

Claims

1. A method for preparing a water-soluble complex, comprising: a. Mixing a compound with a non-nutritive sugar in one or more solvents, wherein the compound is an anthracycline or a pharmaceutically acceptable salt, solvate, cocrystal, hydrate, or polymorph; and b. Remove the solvent to obtain a powder composition; c. Dissolve the powder composition in water, optionally dissolving it in water together with an acid, to obtain a water-soluble complex, and optionally filter the water-soluble complex; The compounds in the water-soluble complex have improved solubility compared to those not in the water-soluble complex.

2. The method of claim 1, further comprising drying the water in the water-soluble complex.

3. The method of claim 1, wherein the compound and the non-nutritive sugar are present in a molar ratio of about 0.1:1.0 to about 1.0:20.

0.

4. The method of claim 1, further comprising a nonionic surfactant in step a to form a water-soluble complex containing a nonionic surfactant, a non-nutritive sugar, and a compound.

5. The method of claim 4, wherein the nonionic surfactant is a polysorbate surfactant or a poloxamer surfactant, and wherein the molar ratio of the compound to the nonionic surfactant is from about 1:0.5 to about 1:5.

0.

6. The method of claim 2, wherein the compound and the non-nutritive sugar are present in a molar ratio of about 1.0:10.

0.

7. The method of any one of claims 1 to 6, wherein the non-nutritive sugar is stevia glycoside, durcuric acid A, durcuric acid B, sucrose, D-fructose, sucralose, riboboroside A, riboboroside B, riboboroside D, stevioside, stevia, n-octyl glucose, n-lauryl-β-D-maltodextrin, advantamé®, neotame®, semathymidine, saccharin, sucralose, stevioside, monk fruit, aspartame, acetylsupanose, or allulose.

8. The method according to any one of claims 1 to 6, wherein the solvent is ethanol, water, methanol, or a combination thereof.

9. The method of any one of claims 1-6, wherein the solvent is ethanol, and is about 70% to about 95% ethanol.

10. The method of claim 8, wherein the solvent is 95% ethanol.

11. The method of any one of claims 1-10, further comprising drying the water-soluble complex dissolved in water.

12. The method of claim 1, wherein step a) and / or step b) further comprises adding a pharmaceutically acceptable acid to a solvent or water.

13. The method of claim 12, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutamate, 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.

14. The method of any one of claims 1-13, wherein the anthracycline compound or its pharmaceutically acceptable salt, solvate, hydrate, eutectic or polymorph is daunorubicin, doxorubicin, epirubicin, edabacin, mitoxantrone, pentorubicin, aldoxorubicin, anamycin, purcamycin, pirarubicin or arubicin.

15. A water-soluble complex prepared by any one of claims 1 to 14.

16. The water-soluble complex of claim 15, wherein the water-soluble complex is stable in water at a pH of about 8.5 and / or a pH of 4.0 for at least two hours.

17. A pharmaceutically acceptable composition comprising the water-soluble complex of any one of claims 15 or 16, wherein, when measured at 20°C, the compounds in the water-soluble complex have at least a 50% improvement in water solubility compared to the individual compounds.

18. The pharmaceutically acceptable composition of claim 17, wherein the non-nutritive sugar is present in a daily dose not exceeding 280 mg.

19. The pharmaceutically acceptable composition of claim 17, wherein the weight ratio of said compound to non-nutritive sugar is from about 0.1:1.0 to about 1:10.

0.

20. The pharmaceutically acceptable composition of claim 17, wherein the weight ratio of said compound to non-nutritive sugar is from about 1.0 to about 10.

0.

21. The pharmaceutically acceptable composition according to any one of claims 17 to 20, wherein the anthracycline compound or its pharmaceutically acceptable salt, solvate, hydrate, eutectic or polymorph is daunorubicin, doxorubicin, epirubicin, edabacin, mitoxantrone, pentorubicin, aldoxorubicin, anamycin, purcamycin, pirarubicin, arubicin, and optionally further comprises citric acid, HCl or KCl.

22. The pharmaceutically acceptable composition of any one of claims 17 to 20, wherein the nonnutritive sugar is one or more of stevia glycoside, durcuric acid A, durcuric acid B, sucrose, D-fructose, sucralose, riboboroside A, riboboroside B, riboboroside D, stevioside, stevia, n-octyl glucose, n-lauryl-β-D-maltodextrin, advantamé®, neotame®, semathyme, saccharin, sucralose, stevioside, monk fruit, aspartame, acetylsupanose, or allulose.

23. The pharmaceutically acceptable composition of claim 21, wherein the anthracycline is doxorubicin or a pharmaceutically acceptable salt, solvate, hydrate, eutectic or polymorph thereof.

24. The pharmaceutically acceptable composition of claim 23, wherein the anthracycline salt is doxorubicin hydrochloride.

25. A pharmaceutically acceptable composition of any one of claims 17 to 20, used in the preparation of feed, tablets, capsules, capsule-shaped tablets, suppositories, or food additives.

26. A kit for preparing a liquid formulation of a water-soluble complex, comprising a water-soluble complex of any one of claims 15 or 16 and a sterile liquid, and optionally instructions for mixing the powdered formulation and the sterile liquid to prepare the liquid formulation.

27. A method of treating a cancer patient, the method comprising administering to the patient in an amount sufficient to inhibit cancer progression a water-soluble complex of any one of claims 15 or 16 or a pharmaceutically acceptable composition of any one of claims 17 to 25.

28. Use of the water-soluble complex of any one of claims 15 or 16 in the preparation of a medicament for treating cancer.

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