COMPOSITIONS AND METHODS FOR IMPROVING THE SOLUBILITY OF CANNABINOIDS AND ENDOCANNABINOIDS TECHNICAL FIELD [0001] Disclosed are water-soluble soluble complexes comprising a surfactant and a drug compound, optionally including a non-nutritive sugar (“sugar”). The drug compound is one or more cannabinoid/endocannabinoid, which forms a complex with the surfactant. The water-soluble complex can further or optionally comprise a non-nutritive sugar/sweeten. Significantly better water solubility is provided by the drug in the complex as compared to the drug alone, thereby enhancing the drug’s suitability for administration to a subject. Also disclosed are methods for making such complexes and compositions comprising such complexes. RELATED APPLICATIONS [0002] The International PCT Application claims benefit of U.S. Provisional Applications 63/582,433, 63/613,411, and 63/623,803 filed respectively on September 13, 2023, December 21, 2023, and January 22, 2024, the contents of which are incorporated herein for all purposes. BACKGROUND [0003] The water solubility of compounds can play a critical role in the development of those compounds and their commercial utility, especially in the pharmaceutical industry. Water solubility plays an important role in the compound’s effectiveness as a compound or drug in the subject administered the compound or drug. Compounds with poor water solubility also lead to other challenges with the compound’s metabolism, permeability, interaction(s) with drugs or other compounds, and the need to extend compound release. Limited water solubility can lead directly to insufficient uptake, poor C
max properties (e.g., maximum blood concentration), and the like. If a compound is not sufficiently soluble, it may not be fully absorbed into a subject’s blood circulation and then can be expelled from the subject before reaching the site of action (e.g., Ganesan et al., “Solubility: a speed-breaker on the drug discovery highway,” Bioequiv. Availab.3(3): 56-8, 2017, Editorial). [0004] The water 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 water solubility can lead directly to insufficient drug uptake, poor C
max properties (e.g., maximum blood concentration), and the like. If a compound or drug is not sufficiently soluble, it may not be fully absorbed into a subject’s blood circulation, which leads to insufficient C
max to be efficacious (e.g., Ganesan et al., 2017). [0005] Cannabinoids and endocannabinoids can have varying levels of solubility. For example, cannabidiol and delta-9-THC both are about 6% bioavailable orally because of their low solubility in water. This makes the use of a cannabinoid or endocannabinoid for purposes of administering to a subject (e.g., an animal) limited due to the poor solubility of cannabinoids/endocannabinoids. Identifying a methodology that renders drug compounds, such as poorly soluble cannabinoids and endocannabinoids, substantially more soluble in aqueous environments remains needed. SUMMARY [0006] Finding new ways of making existing drug compounds more soluble, especially for poorly soluble compounds, has been long sought for both FDA-approved drugs as well as other compounds where an acceptable solubility has been a roadblock for commercialization. Disclosed are water-soluble complexes of a drug compound, such as a cannabinoid/endocannabinoid and a surfactant optionally in the presence of a non-nutritive sugar, wherein the drug in the form of the complex significantly enhances the water solubility of the drug compound, especially if making a compound for oral delivery. The water-soluble complex can comprise a surfactant and optionally one or more non-nutritive sugars. One embodiment contemplates making a water-soluble complex using one or more non-nutritive sugars at a ratio of about 1 to about 10 moles of sugar to each mole of the compound as well as any value between one and ten. In further embodiments, a water-soluble sugar-compound complex can be formed with the assistance of one or more polysorbate surfactants (PSS) or Poloxamer surfactants (PXS). Also disclosed are methods for making such complexes and compositions including pharmaceutical compositions comprising such complexes. [0007] Provided herein are methods of improving the water solubility of a compound (drug compound) by a means that creates complexes of the compound with a non-nutritive sugar and/or a surfactant. Without being limited to any theory, the stability of these water- soluble complexes is believed to be based on hydrophilic hydrogen bonds and/or host-guest chemistry between the compound and the non-nutritive sugar or the compound and the surfactant, or the compound-surfactant-non-nutritive sugar. In effect, the methods create a stable complex between a pharmaceutically acceptable sugar form of a compound for delivery
(e.g., oral delivery) to a subject. The sugar form of a compound may be a pharmaceutically acceptable sugar form of a compound. In the instance of host-guest chemistry, the compounds join together to form a complex, wherein one compound in the complex is the host and one is the guest. In some cases, in addition to the hydrophilic hydrogen bonds, hydrophobic interactions such as van der Waals interactions between the drug and the non-nutritive sugar (or surfactant or surfactant and non-nutritive sugar), may be involved which can further enhance the stability of the complex comprising the host and guest together. [0008] Typically, the art has shown that compound solubility is frequently improved via specific salt formation of the compound. While such a salt form can enhance its water solubility for the compound alone, the resulting salt may still be considered poorly water- soluble. Accordingly, the methods and complexes described herein can be used with the free base or acid of a compound as well as its salt form. However, generally, the salt forms of a compound will occupy some of the hydrogen bonds, making the salt form of the compound perhaps less soluble when used with one or more non-nutritive sugars. Also contemplated are solvates, co-crystals, and polymorphs of the compounds listed herein. [0009] Described herein are sugars that can be complexed to a compound by a process described herein that results in a complex having a greater water solubility than the compound not found in or as a part of such a complex. In some embodiments, still further enhancements in water solubility can be achieved by adding an acid, e.g., a pharmaceutically acceptable acid, either at step 1 and/or step 2 of the methods described herein. [0010] The drug compounds complexed to the non-nutritive sugar can be drug compounds such as small pharmaceutical compounds but can include non-drug compounds such as cannabinoids/endocannabinoids that benefit from complexation. [0011] Provided herein are surfactant-cannabinoid/endocannabinoid complexes that may comprise one or more non-nutritive sweeteners (also referred to as non-nutritive sugars), wherein the cannabinoid/endocannabinoid is the drug compound, and wherein the solubility of the complex is significantly enhanced as compared to the drug compound not complexed with the surfactant and optionally further with the non-nutritive sweetener. In certain embodiments, the non-nutritive sweetener can be a diterpene glycoside (DTG). Provided herein are surfactant-sugar-cannabinoid/endocannabinoid complexes of one or more diterpene glycosides (DTG) or other non-nutritive with a poorly soluble drug (PSD) or drug compound wherein the drug is a cannabinoid/endocannabinoid, and wherein the solubility of the water-soluble complex is significantly enhanced as compared to the drug compound when not complexed with a surfactant and optionally further with a non-nutritive sugar present.
[0012] One embodiment disclosed is a method of improving a compound’s water solubility which method comprises: admixing (e.g., stirring) the compound with a surfactant in the optional presence of a non-nutritive sugar in a solvent or co-solvent (e.g., for example, 95% ethanol is a co-solvent having ethanol and water); and removing the solvent to obtain a powder composition comprising the surfactant, the compound, and optionally the non-nutritive sugar. The dried powder is then dissolved in water and optionally filtered producing the water-soluble complex. If a non-nutritive sugar is present, the mole ratio of a sugar to a drug compound can be present in a mole ratio of about 1:1 to about 1:20 or from about 1 to about 10, and any value in between those ranges from 1 to 20. For example, stevia can be used at a ratio of stevia to a compound of 3:1. In another embodiment, two sugars can be used to form a complex with the compound and the surfactant, such as a combination of rubusoside and stevioside in the presence of a drug compound, e.g., a poorly soluble compound, and 95% ethanol (or another solvent). For the drug compounds, the goal would be to keep the amount of the non-nutritive sugar below the GRAS (the FDA’s Generally Regarded As Safe limits) recommended limit for each sugar. Another aspect contemplates the use of isopropyl alcohol as one of the solvents for use topically. [0013] A non-nutritive sugar used in the disclosed methods binds through hydrogen bonds to a cannabinoid/endocannabinoid and/or in the form of a complex, wherein the non- nutritive sugar can be rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, rebaudioside A, rebaudioside B, rebaudioside D, stevioside, stevia, n-octyl glucose, or n- dodecyl-β-D-maltoside as well as the other sugars listed herein. [0014] A method disclosed herein uses a solvent or a co-solvent to dissolve the drug compound and surfactant optionally further in the presence of one or more non-nutritive sugars. The solubility of the surfactant and drug compound (and optional the non-nutritive sugar) creates new chemical bonding between and among these components. As the solvent or co- solvent is removed, the the chemical bonds remain for the water-soluble complex allowing the drug compound to have improved water solubility compared to the drug compound in non- complexed form. [0015] In one aspect, the solvent can be ethanol, methanol, water, hexane, or another pharmaceutically acceptable solvent or mixtures thereof. Co-solvents can include water and an alcohol such as methanol, ethanol, or isopropanol. Higher-order solvent mixtures include, by way of example, water, methanol, and ethanol. The additional solvents can be ethanol, methanol, water, hexane, a co-solvent, or another pharmaceutically acceptable solvent. Illustrative examples of cosolvents can include the following: 50% to just less than 100%
solvent and water or about 50% to less than 100% ethanol with the remainder being methanol or 50% to less than 100% ethanol and up to about 50% to about 0.001% methanol and any value in methanol within that range. In another embodiment, instead of water, a buffer may be used. Additional solvents are listed herein. [0016] Another embodiment contemplates a powdered formulation including a dried form of the water-soluble drug complex. An embodiment contemplates that a water-soluble surfactant-sugar-compound complex formed by the method can have a weight ratio of the drug compound to sugar of about 0.1:1.0 to about 1.0:20.0, or from about 1.0:1.0 to about 1.0:20.0 and any 0.1 value in between 0.1 to 1:20.0. Alternatively, the drug compound and the non- nutritive sugar are present in a mole ratio of about 1:1 to about 1:10 or in a mole ratio of 1:1 to 1:5 or a mole ratio of 1:1 to 1:3 and any 0.01 value between each of these ratios provided herein. [0017] In another embodiment, the drug compound in the complex can be one or more endocannabinoids, one or more cannabinoids, or a combination of one or more endocannabinoids and cannabinoids. [0018] Another embodiment contemplates that the powdered formulation is suitable for reconstitution in water or saline, wherein the complex in the formulation allows for greater water solubility of the drug compound when complexed to the surfactant and optionally a non- nutritive sugar than the drug compound has in the absence of the surfactant and optional non- nutritive sugar to the compound when reconstituted in water, saline, or buffered saline (e.g., phosphate buffered saline, PBS). The water, saline, and buffered saline can optionally be sterile. The reconstituted complex when formulated in sterile water or sterile saline can be administered to a subject intravenously, intraperitoneally, intramuscularly, subcutaneously, nasal spray, sublingually, buccally, intranasally, orally, or buccally. In the case of sublingual formulations, the water-soluble complex can be formulated into a tablet, a strip, a sublingual drop, a sublingual spray, a lozenge, or an effervescent buccal or sublingual tablet for rapid release through the mucosa to include eye drops, inhaled mist or powder, and nebulizer liquid. If the drug-sugar compound is formulated for a nasal spray, the drug is formulated in a metered dose to be insufflated through the nose. [0019] The methods described can use a non-nutritive sugar such as rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, rebaudioside A, rebaudioside B, rebaudioside D, stevioside, stevia n-octyl glucose, or n-dodecyl-β-D-maltoside. The powdered formulation produced by the method would have the non-nutritive sugar, surfactant, and drug compound in the form of a water-soluble complex.
[0020] The method can further comprise dissolving the obtained powder in water and filtering the dissolved obtained powder. The additional solvent or solvents can be ethanol, water, hexane, isopropyl alcohol, or a pharmaceutically acceptable solvent. Solvent examples can include co-solvents such as the following: 50% to near just less than 100% solvent and water or about 50% to less than 100% ethanol with the remainder being methanol or 50% to less than 100% ethanol and up to about 50% to less than 0.001% methanol and any 0.001% value in methanol within that range. In another embodiment, instead of water, a buffer may be used. [0021] In one embodiment, the powdered formulation can be reformulated into a tablet, a capsule, a caplet, a suppository, or a food additive for administration to a subject. The powdered formulation can also be dissolved into water or other pharmaceutically acceptable liquid carrier. Alternatively, the powdered formulation can be reconstituted into a liquid, a syrup, a gel, or a beverage. In another aspect, the powdered compound can be reformulated into a pill, capsule, tablet, or extended-release composition for oral administration to a subject. The formed complex can be further formulated into an extended-release (ER or XR) form that lasts longer in a subject, a sustained-release (SR) form that prolongs the medication’s release from a tablet/capsule over a long period. An SR form differs from controlled-release (CR), formulations wherein the active ingredient is released and a specific rate to maintain a constant medication level. Delayed-release (DR) formulations are also contemplated and include drugs that will release the drug compound, for example, after oral ingestion, only in the small intestines instead of the stomach. Enteric-coated formulations can be an example of a DR form. [0022] The water-soluble complex can also be reformulated into a food product with a drug and/or essential nutrients or vitamins. An “essential nutrient” is a compound that is not synthesized in an organism but is necessary for its survival. For example, vitamin C (ascorbic acid) is not synthesized in humans and some animals, but certain animals and some plants can synthesize it. Essential nutrients include vitamins, minerals (elements), proteins, fats, water, and carbohydrates. Essential elements include chromium, copper, zinc, selenium, molybdenum, and iodine (Mehri, “Trace Elements in Human Nutrition (II) – An Update” Int. J. Prev. Med.11: 2 (2020). Essential nutrients can vary based on the subject. [0023] Another embodiment contemplates a kit for making a liquid formulation of the powdered formulation comprising the water-soluble complex and a sterile liquid and optionally instructions for admixing the powdered formulation and the sterile liquid to make the liquid formulation. Such kits may further comprise a means of delivering the formulation (a syringe or pen) and/or directions for making and using the liquid formulation.
[0024] One embodiment contemplates a water-soluble, sugar-compound complex comprising a poorly soluble compound (PSD) or drug compound and a non-nutritive sugar (e.g., a DTG or other sugar), wherein the PSD or drug compound has hydrogen bonding of the compound to the non-nutritive sugar forming a water-soluble complex of formula (I): [Sugar]
pDrug (I) wherein p is the molar ratio of up to about 20 moles of the non-nutritive sugar for each mole of said drug compound whether poorly soluble or not. The non-nutritive sugar can be one or more of rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, rebaudioside A, rebaudioside B, rebaudioside D, stevioside, stevia, n-octyl glucose, n-dodecyl-β-D-maltoside, ADVANTAME®, NEOTAME®, thaumatin, saccharin, sucralose, a stevio glycoside, Lou Han Guo, aspartame, acesulfame potassium, or allulose. In all cases herein, the term “improved water solubility” or “improved solubility” is determined in water or 0.9% saline maintained at 20 ºC. [0025] Another aspect is a water-soluble sugar-compound complex comprising a drug compound, such as a poorly soluble cannabinoid and/or endocannabinoid and a diterpene glycoside (DTG) sugar, wherein the compound has hydrogen bonding of the compound to the non-nutritive sugar forming a sugar-compound complex of formula (II): [DTG]
pCompound (II), wherein p is the molar ratio of up to about 20 moles of the non-nutritive sugar (DTG) for each mole of said drug compound (“Compound”), wherein the non-nutritive sugar is one or more of rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, rebaudioside A, rebaudioside B, rebaudioside D, stevioside, stevia, or a stevio glycoside. The drug compound can be one or more cannabinoids, endocannabinoids, or a combination thereof. The p can be from about 1.0 to about 12.0, or from about 1.5 to about 10.0. The water-soluble complexes contemplated also contemplate that the poorly soluble compound or other drug compound can be a salt form of the compound, however, without being limited to any theory, it is possible that salt forms may be less preferred given the salt ion will occupy positions otherwise taken by a hydrogen bond in the complex when using a non-nutritive sugar and drug compound in the absence of a surfactant. The water-soluble complex formation can further be assisted by the presence of an acid or a base. [0026] In another embodiment, water-soluble non-nutritive sugar-compound complexes comprising one or more polysorbate surfactants (PSS) or Poloxamer surfactants (PXS) described herein can be represented by Formula III as follows:
[ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^]
^^^^[ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^]
^^^^ ^^^^ ^^^^ ^^^^ ^^^^ (III) wherein the non-nutritive sugar, PSS/PXS, and the drug compound (i.e., a cannabinoid/endocannabinoid) are as defined herein. p can be an integer from 1 to 5. The non- nutritive sugar is any of the non-nutritive sugars indicated herein. Ionic surfactants can also be substituted for the PSS or PSX indicated in Formula III. Certain ionic surfactants may be substituted for non-ionic surfactants such as DATEM (diacetyl tartaric acid ester of mono- and diglycerides; E number E472e). Other ionic surfactants can include sodium stearate and sodium caseinate. [0027] In one embodiment, the complexes described herein can be represented by
Formula IV as follows: [
^^^^ ^^^^ ^^^^ ^^^^ ^^^^] ^^^^[ ^^^^ ^^^^ ^^^^] ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ (IV) where the non-nutritive sugar, PXS, and a drug compound (i.e., a cannabinoid/endocannabinoid) are as defined herein. p can be an integer from 1 to 5 and q can be from 0.1 to 5. The non-nutritive sugar can be any one or more of the non-nutritive sugars indicated herein. Ionic surfactants as those listed herein can be substituted for PXS in Formula IV. Exemplary ionic surfactants include but are not limited to DATEM, sodium caseinate, and sodium stearate. [0028] In another embodiment, the complexes described herein can be water-soluble
PSS-compound complexes represented by formula V as follows: [
^^^^ ^^^^ ^^^^] ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ (V) where PSS and drug compound (i.e., a cannabinoid/endocannabinoid ) are as defined herein. p can be an integer from 1 to 5. Other ionic or non-ionic surfactants can also be substituted for the PSS surfactants of Formula V. Exemplary ionic surfactants include but are not limited to DATEM, sodium caseinate, and sodium stearate. [0029] In another embodiment, the complexes described herein can be water-soluble
PXS-compound complexes represented by formula VI as follows: [
^^^^ ^^^^ ^^^^] ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ (VI) where PXS and drug compound (i.e., a cannabinoid/endocannabinoid ) are as defined herein. p can be an integer from 1 to 5. Other ionic or non-ionic surfactants can also be substituted for the PXS surfactants of Formula VI. Ionic surfactants contemplated include but are not limited to sodium stearate, sodium caseinate, and DATEM. [0030] In some embodiments, the water-soluble complex contains a sugar in a daily
unit dose is no more than about 5 mg/kg. Alternatively, the daily unit dose of a non-nutritive sugar in the complex is no more than about 280 mg. [0031] Another embodiment contemplates the water-soluble surfactant- cannabinoid/endocannabinoid complex (optionally with a non-nutritive sugar) after the two- step method being stable when dissolved in water at pH 8.5 for at least about 2 hours. Alternatively or additionally, the water-soluble cannabinoid/endocannabinoid complex is stable in water at pH 4 for at least 2 hours. Alternatively or additionally, the water-soluble cannabinoid/endocannabinoid complex is stable at 30 °C. for at least 90 days when dried to a powder. When a water-soluble complex as described herein meets any of these stability tests, the water-soluble complex is deemed to be a stable complex. [0032] In one contemplated method, the water-soluble cannabinoid/endocannabinoid complex is solubilized in saline or other pharmaceutically acceptable buffer. [0033] Another embodiment contemplates the water-soluble cannabinoid/endocannabinoid complex of any of the embodiments disclosed herein in the form of a powder, a tablet, an orally disintegrating tablet, a capsule, a liquid, a drop, a nasal spray, a topical, (e.g., gel, lotion, oil), a gel, a thin film, a lozenge, a chewable pill or gummy, an effervescent powder or tablet, an emulsion, or formulated for parenteral administration. Alternatively, the water-soluble cannabinoid/endocannabinoid complex can be a formulation prepared for parenteral administration and can be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, or intravenously. A further embodiment contemplates the water-soluble cannabinoid/endocannabinoid complex formulated as a thin film, an effervescent powder or tablet, an inhalable formulation, a syrup, a solution, an elixir, an emulsion, a chewing gum, a gummy, a lollipop, a sublingual drop, a soft gel, or a tincture. [0034] Another embodiment contemplates a water-soluble complex comprising a cannabinoid/endocannabinoid, a surfactant, and optionally a non-nutritive sugar wherein the water-soluble complex comprises: a molar ratio of about 3 moles of the non-nutritive sugar (if present) for each mole of said drug compound, wherein the non-nutritive sugar is one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; wherein said water-soluble complex is stable in water at pH 8.5 and pH 4.0 for at least 2 hours each; and further 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. [0035] Another method contemplated is of making a water-soluble complex comprising a non-nutritive sugar and a drug compound, the method comprising the steps of admixing, in a solvent (e.g., at least 85% ethanol (or at least 90% or 95%)), a surfactant and/or
the non-nutritive sugar with the drug compound, wherein the in a molar ratio of the drug compound to the non-nutritive sugar is from about 1.0 to about 5.0 moles of the non-nutritive sugar for each mole of said drug compound. Solubilization of the water-soluble complex can be determined, for instance, by nuclear magnetic resonance spectroscopy (NMR). The non- nutritive sugar can be one or more non-nutritive sugars of rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; 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 non-nutritive sugar used in the method is rubusoside or stevioside. [0036] The drug compound that can be used in the method of making the water-soluble complex can be any one or more of a cannabicyclol, a cannabichromene, a cannabielsoin (CBE and a metabolite of cannabidiol), a cannabitriol (CBT), a cannabidiol, a cannabigerol, a cannabinol, a cannabinodiol (CBND, also known as cannabidinodiol), a delta- tetrahydrocannabinol, a delta-tetrahydrocannabinol, or a pharmaceutically acceptable salt of any thereof. The drug compound can also be any one of delta-8-tetrahydrocannabinol (Δ8- THC), delta-8-tetrahydrocannabinolic acid (Δ8-THCA), delta-9-tetrahydrocannabinol (Δ9- THC or THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), and tetrahydrocannabinolic acid (THCA), or cannabiidiolic acid (CBDA). 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, cream, tincture, or lotion for purposes of administration. [0037] The method of preparing the water-soluble complex may further require the presence of a pharmaceutically acceptable acid to be added in the first admixing step or the water-dissolving step (step 2) or in both steps. The acid should be present in a sufficient amount 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. [0038] The method of making the water-soluble complex can admix a molar ratio of about 1 to about 12 moles of a non-nutritive sugar for each mole of the said drug compound. The non-nutritive sugar can be any of the non-nutritive sugars 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 non-nutritive sugar for each mole of the
drug compound, or from about 3 to about 5 moles of the non-nutritive sugar to each mole of the drug compound. In another embodiment, the formed water-soluble complex from the method can comprise a molar ratio of about 3 moles of the non-nutritive sugar for each mole of the said drug compound, as well as any 0.1 amount between 1:1.0 and 1:12.0. [0039] A water-soluble complex of one or more cannabinoids/endocannabinoids can be created in the presence of a surfactant and optionally further with a non-nutritive sugar as discussed herein. Exemplary surfactants are nonionic surfactants such as polysorbates and poloxamers. Other surfactants contemplated are ionic surfactants such as DATEM, sodium caseinate, and sodium stearate. Polysorbate surfactants (PSS) are derived from ethoxylated sorbitan esterified with fatty acids. Commercially available examples of suitable polysorbate surfactants include 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” refers to the major fatty acid associated with the molecule. For instance, “20” indicates monolaurate, and “80” indicates monooleate. [0040] Another type of surfactant that can be used to create a water-soluble complex with a cannabinoid/endocannabinoid is a poloxamer surfactant (PXS). PXS surfactants 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). PXSs 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. In an embodiment, the PXS is Poloxamer 188 (Kolliphor® P 188, Pluronic® F-68, Lutrol® F68, and Synperonic® F68). Preferably, the poloxamer surfactant is approved for animal consumption or human consumption by an appropriate governmental regulatory agency. [0041] Additional suitable surfactants contemplated for preparing a complex with a cannabinoid/endocannabinoid optionally in the presence of a non-nutritive sugar include non- ionic and ionic surfactants. Non-ionic surfactants can be poloxamers and polysorbates. Ionic surfactants can be sodium stearate, sodium caseinate, and diacetyl tartaric acid ester or mono- and diglycerides (DATEM or E472e).
[0042] Disclosed and contemplated herein is a water-soluble complex comprising a nonionic surfactant, wherein the nonionic surfactant can be a polysorbate or poloxamer surfactant in combination with a drug compound, and optionally a non-nutritive sugar, which water-soluble complex comprises: a molar ratio of up to about 12 moles of the non-nutritive sugar and up to about 12 moles of the nonionic surfactant (e.g., polysorbate (PSS) or poloxamer (PXS) surfactant) for each mole of the drug compound, wherein the non-nutritive sugar can be one or more of rubusoside, dulcoside B, dodecyl-β-D-maltoside, stevioside, or rebaudioside A. When the nonionic surfactant is a polysorbate surfactant said surfactant can be one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, and Polysorbate 80. If the nonionic surfactant selected is a poloxamer, the poloxamer surfactant can be Poloxamer 188. Preferably the resulting water-soluble complex has an increase in water solubility as a complex over the drug compound when it is not in the form of the complex. Preferably, the water- soluble complex has at least about a two to five-fold increase in the water solubility of said drug compound at 20º C., as compared to the water solubility of said drug compound that is not in said water-soluble complex form; and further provided that a maximum amount of the non-nutritive sugar (if present) is in a daily unit dose of said non-nutritive sugar in the water- soluble complex is no more than about 10 mg/kg. Exemplary non-nutritive sugar used to make the water-soluble complex can be stevioside or rubusoside, and the PSS can be Polysorbate 20 and/or Polysorbate 80 or the PXS is Poloxamer 188. Ionic surfactants like DATEM and similar compounds can also be used. [0043] Another water-soluble complex contemplates using a drug compound that is one or more cannabinoids selected from the group consisting of cannabicyclols (CBLs), cannabichromenes, cannabielsoins, cannabitriols, cannabidiols, cannabigerols, cannabinols, cannabinodiols, and certain delta-tetrahydrocannabinols or combinations thereof. Exemplary cannabinoids are those that have beneficial properties when administered to an animal or human. [0044] In another embodiment, the water-soluble complex is comprised of a non- nutritive sugar selected from the group of rubusoside, rebaudioside A, dodecyl-β-D-maltoside, dulcoside B, stevioside or any combination or permutation thereof, and the polysorbate surfactant is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, and Polysorbate 80. [0045] In another embodiment, the water-soluble sugar-cannabinoid/endocannabinoid complex is comprised of a non-nutritive sugar selected from the group of rubusoside, rebaudioside A, dodecyl-β-D-maltoside, dulcoside B, or stevioside or any combination or
permutation thereof, and the poloxamer surfactant is Poloxamer 188. [0046] Also contemplated is a water-soluble sugar-cannabinoid/endocannabinoid complex comprising an optional non-nutritive sugar, a polysorbate or poloxamer surfactant, and a drug compound, which cannabinoid/endocannabinoid complex comprises: a molar ratio of up to about 12 moles of the non-nutritive sugar and up to about 12 moles of the surfactant for each mole of said poorly water-soluble drug or drug compound, wherein the optional non- nutritive sugar (also referred to herein as a non-nutritive sweetener) is one or more of rubusoside, dulcoside B, dodecyl-β-D-maltoside, stevioside, or rebaudioside A, and the surfactant is a nonionic surfactant that is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, and Polysorbate 80, or a poloxamer surfactant and the poloxamer surfactant is Poloxamer 188, provided that said water-soluble sugar- cannabinoid/endocannabinoid complex has improved water solubility as compared to the drug compound not in the form of the complex. Preferably the water solubility of the complex improves the drug compound’s solubility by at least a two, three, four, or five-fold as compared to the drug compound not in the form of the complex when measured at 20º C. and further provided that a maximum amount of the non-nutritive sugar (if present in the complex) is in a daily unit dose of no more than about 10 mg/kg. The non-nutritive sugar used to make the water-soluble complex can be stevioside, and the PSS can be Polysorbate 20 and/or Polysorbate 80 or the PXS is Poloxamer 188. [0047] Another water-soluble cannabinoid/endocannabinoid complex contemplates using one or more drug compound selected from cannabinoids such as cannabicyclols (CBLs), cannabichromenes, cannabielsoins, cannabitriols, cannabidiols, cannabigerols, cannabinols, cannabinodiols, and certain delta-tetrahydrocannabinols (delta-9 tetrahydrocannabinol is not included). Exemplary cannabinoids for use with the method include those that have beneficial properties when administered to a human or an animal and/or that have limited water solubility. [0048] In another embodiment, the water-soluble cannabinoid/endocannabinoid complex is comprised of an optional non-nutritive sugar which is selected from rubusoside, rebaudioside A, dodecyl-β-D-maltoside, dulcoside B, or stevioside or any combination or permutation thereof, and the polysorbate surfactant is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60. Polysorbate 65, and Polysorbate 80. [0049] In another embodiment, the water-soluble cannabinoid/endocannabinoid complex is comprised of an optional non-nutritive sugar selected from the group of rubusoside, rebaudioside A, dodecyl-β-D-maltoside, dulcoside B, or stevioside or any combination or permutation thereof, and the surfactant is a poloxamer surfactant is Poloxamer 188. In another
embodiment, the water-soluble sugar-cannabinoid/endocannabinoid complex is comprised of the non-nutritive sugar stevioside and the poloxamer surfactant is Poloxamer 188. [0050] In a further embodiment, the amount of the non-nutritive sugar in the daily unit dose administered to a subject amounts to no more than about 5 mg/kg of subject weight if the non-nutritive sugar is in the water-soluble complex. In another embodiment, the water-soluble cannabinoid/endocannabinoid complex having a non-nutritive sugar comprises an amount of sugar in the daily unit dose of no more than about 280 mg. [0051] In another embodiment, the water-soluble cannabinoid/endocannabinoid complex comprises a molar ratio of about 2 to about 5 moles of the non-nutritive sugar and about 2 to about 5 moles of the polysorbate surfactant for each mole of said poorly water- soluble drug, or drug compound, i.e., a molar ratio Drug:sugar:PSS of about 1:2:2 to about 1:5:5. [0052] In another embodiment, the water-soluble cannabinoid/endocannabinoid complex comprises a molar ratio of about 1 to about 12 moles of a non-nutritive sugar and about 0.5 to about 5 moles of the nonionic surfactant or an ionic surfactant. The nonionic surfactant can be a poloxamer surfactant for each mole of said poorly water-soluble drug (“PSD”) or drug compound, i.e., a molar ratio Drug:sugar:PXS of about 1:1:0.5 to about 1:12:5. In another embodiment, the water-soluble cannabinoid/endocannabinoid complex comprises a molar ratio of about 3 moles of the non-nutritive sugar and about 0.75 moles of a nonionic surfactant, wherein the nonionic surfactant is a poloxamer surfactant for each mole of poorly water-soluble drug or drug compound, i.e., a molar ratio Drug:sugar:PXS of about 4:12:3. [0053] In another embodiment, the water-soluble cannabinoid/endocannabinoid complex comprises a molar ratio (moles of a drug compound or poorly soluble drug compound (PSD) to moles of non-nutritive sugar to moles of a nonionic surfactant such as a polysorbate surfactant in a mole ratio of about 2 to about 4.5 moles of the non-nutritive sugar, and about 2 to about 4.5 moles of the polysorbate surfactant or about 0.5 to about 4.5 moles of the poloxamer surfactant for each mole of said drug compound. In yet another embodiment, the water-soluble cannabinoid/endocannabinoid complex comprises a molar ratio of about 1:1:1 to 1:12:12 or of about 1:1:1 to about 1:10:10 or from about 1:1:1 to 1:5:5 (Drug:Sugar:Surfactant). In another embodiment, the water-soluble cannabinoid/endocannabinoid complex comprises about 3.0 moles of a DTG sugar and 3.0 moles of the nonionic surfactant (e.g., PSS or PXS) or an ionic surfactant for each mole of said poorly water-soluble drug or drug compound, i.e., about 1:3:3 molar ratio. In an embodiment, the water-soluble cannabinoid/endocannabinoid complex comprises about 5.0 moles of the non-nutritive sugar (e.g., a DTG) and 5.0 moles of
a nonionic surfactant (e.g., PSS or PXS) or an ionic surfactant for each mole of said drug compound or poorly soluble drug or drug compound, i.e., about 1:5:5 molar ratio. In another embodiment, the water-soluble cannabinoid/endocannabinoid complex comprises about 3.0 moles of a non-nutritive sugar and 5.0 moles of a nonionic surfactant (e.g., PSS or PXS surfactant) or an ionic surfactant for each mole of the drug compound, i.e., about 1:3:5 molar ratio. Another embodiment contemplates that the water-soluble cannabinoid/endocannabinoid complex remains stable when dissolved in water at pH 8.5 for at least about 2 hours. [0054] In a further embodiment, the water-soluble cannabinoid/endocannabinoid complex is stable when dissolved in water at a pH of 2 - 6 for at least about 2 hours. [0055] A further embodiment contemplates that the water-soluble cannabinoid/endocannabinoid complex is formulated in a gel or syrup and the formulation is stable at 30°C for at least 90 days. [0056] Another embodiment contemplates a freeze-dried water-soluble cannabinoid/endocannabinoid complex or a lyophilized water-soluble cannabinoid/endocannabinoid complex comprising a nonionic surfactant (e.g., PXS or PSS) or an ionic surfactant is formulated for inhalation intake using an electronic cigarette (e-cigarette) device, nebulizer, or similar devices for inhaling a substance. [0057] Another embodiment contemplates a freeze-dried water-soluble cannabinoid/endocannabinoid complex or a lyophilized water-soluble cannabinoid/endocannabinoid complex having a nonionic surfactant (e.g., PSS or PXS) or an ionic surfactant is formulated as a liquid formulation including but not limited to aqueous beverages, water, enhanced water, sports drinks, fruit juices, vegetable juices, smoothies, ready-to-drink teas and coffees, energy drinks, electrolyte-rich or enriched beverages, meal replacement beverages, nutritional supplement beverages, soft drinks, and beverages containing alcohol. [0058] Another embodiment contemplates a water-soluble cannabinoid/endocannabinoid complex comprising a non-nutritive sugar and a poorly water- soluble compound or drug compound, wherein the water-soluble cannabinoid/endocannabinoid complex comprises a molar ratio of about 3 moles of the non- nutritive sugar and about 3 moles of the nonionic surfactant (e.g., PSS or PXS) or an ionic surfactant for each mole of said poorly water-soluble drug or drug compound. Said water- soluble cannabinoid/endocannabinoid complex can comprise a non-nutritive sugar of one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; and wherein the surfactant is a nonionic surfactant or an ionic surfactant. An
Exemplary is PSS of one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, and Polysorbate 80. Preferably the water-soluble cannabinoid/endocannabinoid complex is stable in water at pH 5.0 and pH 2.0 for at least 2 hours each. Preferably the water-soluble cannabinoid/endocannabinoid complex has an improved solubility for the drug compound when in the complex over the drug compound when not in the form of a complex and preferably the water solubility is increased at least a two, three, four, or five-fold when measured at 20 ºC. as compared to the water solubility of said drug compound not in the water-soluble cannabinoid/endocannabinoid complex. Additionally or alternatively, 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. [0059] Another embodiment contemplates a water-soluble cannabinoid/endocannabinoid complex comprising a non-nutritive sugar and a drug compound, which water-soluble sugar-cannabinoid/endocannabinoid complex comprises: a molar ratio of about 2 to about 3 moles of the non-nutritive sugar and about 0.5 moles to about 0.75 moles of a nonionic surfactant (e.g., PSS or PXS) or an ionic surfactant for each mole of said drug compound, wherein the non-nutritive sugar is one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; and wherein when the nonionic surfactant is PXS, it is Poloxamer 188. The water-soluble cannabinoid/endocannabinoid complex preferably is stable in water at pH 5.0 and at pH 2.0 for at least 2 hours each. Optionally or additionally, said water-soluble cannabinoid/endocannabinoid complex has improved water stability and preferably at least a two, three, four, or five (5) fold increase in the water solubility of said drug compound at 20º C when in the form of a water-soluble complex as compared to the water solubility of said drug compound not in the form of the water-soluble cannabinoid/endocannabinoid complex. Optionally or additionally, the water-soluble cannabinoid/endocannabinoid complex should have a maximum amount of the non-nutritive sugar in a daily unit dose of said water-soluble cannabinoid/endocannabinoid complex is no more than about 280 mg. [0060] Another aspect contemplates a method of making a water-soluble cannabinoid/endocannabinoid complex comprising a non-nutritive sugar, an ionic surfactant or a nonionic surfactant (e.g., a PSS or PXS surfactant), and a drug compound, the method comprising the steps of admixing, in at least 85% ethanol (or at least 90% or 95%), the non- nutritive sugar, the nonionic surfactant (e.g., a PSS or PXS) or an ionic surfactant and the drug compound in a molar ratio of from about 1.0 to about 12.0 moles of the non-nutritive sugar and from about 1.0 to about 5.0 moles of the nonionic surfactant if the surfactant is a PSS surfactant,
or about 0.5 to about 1 mole of a PXS surfactant, for each mole of said cannabinoid/endocannabinoid compound until solubilized. The solubilized complex is then dried and dissolved in water (step 2) yielding the water-soluble complex. The formation of the water-soluble cannabinoid/endocannabinoid complex can optionally be determined by nuclear magnetic resonance spectroscopy (NMR). The non-nutritive sugar in said water-soluble cannabinoid/endocannabinoid complex can be one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside. The water-soluble cannabinoid/endocannabinoid complex having the nonionic surfactant can use a polysorbate surfactant of one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60. Polysorbate 65, and Polysorbate 80. Alternatively, if the water-soluble cannabinoid/endocannabinoid complex comprises a poloxamer surfactant, it can be Poloxamer 188. The admixing step of the solvent, drug compound, non-nutritive sugar, and nonionic surfactant or an ionic surfactant can be optionally performed with a pharmaceutically acceptable acid (step 1). The water-soluble cannabinoid/endocannabinoid complex is then dried and dissolved in water. In some embodiments, the disclosed method utilizing a surfactant or a surfactant with a non-nutritive sugar, results in cannabinoid/endocannabinoid solubility when in the form of a complex is greater than at least 20%, as determined by NMR spectroscopy. In some embodiments, cannabinoid/endocannabinoid solubility achieved in a method described herein is improved over the drug compound not in a complex by at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, and up to 100% solubility, as determined by NMR spectroscopy and as compared to solubility of the cannabinoid/endocannabinoid in water when not in a complex formed by any of the methods described herein. A further method contemplates that if a non- nutritive sugar is used in the method the non-nutritive sugar is stevioside and the PSS is Polysorbate 20 or Polysorbate 80. A further method contemplates that if a non-nutritive sugar is used in the method, the sugar is stevioside and a poloxamer surfactant, wherein the PXS is Poloxamer 188. A further method contemplates that the solvent, drug compound, non-nutritive sugar, and surfactant (e.g., PSS or PXS) solution of the admixing step of step 1 is heated, for instance to about 60°C., to melt the PSS or PXS and facilitate solubilizing the drug compound in the admixture solution. The drug compound used in the methods described can be a cannabicyclol, a cannabichromene, a cannabielsoin, a cannabitriol, a cannabidiol (CBD), a cannabigerol, a cannabinol, a cannabinodiol, a delta-tetrahydrocannabinol, a delta- tetrahydrocannabinol, or a pharmaceutically acceptable salt of any thereof. The poorly water-
soluble drug or drug compound can also be any one of delta-8-tetrahydrocannabinol (Δ8-THC), delta-8-tetrahydrocannabinolic acid (Δ8-THCA), delta-9-tetrahydrocannabinol (Δ9-THC or THC), Δ8-THC acetate ester (delta-8 THCO), Δ9-THC acetate ester (delta-9 THCO), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), and a tetrahydrocannabinolic acid (THCA), or cannabiidiolic acid (CBDA). The method further can comprise drying the water-soluble complex to form a solid. [0061] The method of making the water-soluble complex can admix a molar ratio of about 1 to about 12 moles of a non-nutritive sugar and about 1 to about 12 moles of a PSS when the surfactant is PSS, or about 0.5 to about 5 moles of the PXS when the surfactant is PXS, for each mole of the drug compound. The non-nutritive sugar can be any of the non-nutritive sugars listed herein, for example, stevioside or rubusoside. A PSS can be any of the polysorbate surfactants discussed herein, for example, Polysorbate 20, and Polysorbate 80, or a poloxamer. A PXS can be any poloxamer surfactant, such as Poloxamer 188. Alternatively, the water- soluble complex made by the method can have a molar ratio of about 2 to about 10 moles of any one or more non-nutritive sugars and about 2 to about 10 moles of a PSS, for each mole of said drug compound (i.e., about 1:2:2 to about 1:10:10 molar ratio Drug:sugar:PSS). Alternatively, the water-soluble complex made by the method can have a molar ratio of about 1 to about 12 moles of one or more non-nutritive sugars and about 0.5 to about 5 moles of a PXS, for each mole of said drug compound (i.e., about 1:1.0:0.5 to about 1:12.0:5.0 molar ratio Drug:sugar:PXS). In another embodiment, the formed water-soluble complex from the method can comprise a molar ratio of about 3 moles of one or more non-nutritive sugars and about 5 moles of a PSS for each mole of said drug compound (about 1:3:5 molar ratio of Drug:sugar:PSS), as well as any 0.1 amount between about 1:1.0:1.0 and about 1:12.0:12.0. In another embodiment, the formed water-soluble complex produced from the method, can comprise a molar ratio of about 3 moles of one or more non-nutritive sugars and about 0.75 moles of a PXS for each mole of said drug compound (about 1:12.0:3.0 molar ratio of Drug:sugar:PXS), as well as any 0.1 amount between about 1:2.0:0.5 and about 1:12.0:4.0, including any 0.1 amount between about 1:4.0:0.5 and about 1:12.0:3.0. [0062] These and other embodiments will be apparent to those of skill in the art upon reading the specification. BRIEF DESCRIPTION OF THE FIGURES [0063] FIG. 1 depicts the NMR results for Example 2 (H-006-084). NMR Recorded
on a 400 MHz nuclear magnetic resonance spectrometer (mr400 instrument; 399.979 MHz,
1H NMR spectrum, 1D in D
2O; reference to external acetone @ 2.225 ppm; temp.25.9 C.; actual temp = 27.0 C.; oneNMR probe). The NMR scan parameters were: Sweep Width (Hz) = 4807.69; Acquisition Time (s) = 3; Relaxation Delay(s) = 2; Pulse Sequence = PRESAT; Digital Res. (Hz/pt) = 0.07; Hz per mm (Hz/mm) = 20.03; and Completed Scans = 16. NMR suggests at least 70% solubility of the drug compound in complex form. [0064] FIG.2 depicts the NMR results for Example 3 (H-006-135). NMR Recorded on a 400 MHz nuclear magnetic resonance spectrometer (mr400 instrument; 399.979 MHz,
1H NMR spectrum, 1D in D
2O; reference to external acetone @ 2.225 ppm; temp.25.9 ºC.; actual temp = 27.0 ºC.; oneNMR probe). Fig. 2 depicts approximately 100% solubility of the complex. [0065] FIG.3 depicts the NMR results for Example 5 (H-006-136). NMR Recorded on a 400 MHz nuclear magnetic resonance spectrometer (mr400 instrument; 399.979 MHz,
1H NMR spectrum, 1D in D
2O; reference to external acetone @ 2.225 ppm; temp.25.9 ºC.; actual temp = 27.0 ºC.; oneNMR probe). Fig. 3 depicts approximately 100% solubility of the complex. [0066] FIG.4 depicts the NMR results for Example 9 (H-006-139). NMR Recorded on a 400 MHz nuclear magnetic resonance spectrometer (mr400 instrument; 399.979 MHz,
1H NMR spectrum, 1D in D
2O; reference to external acetone @ 2.225 ppm; temp.25.9 ºC.; actual temp = 27.0 ºC.; oneNMR probe). Fig.4 indicates no soluble drug is present. [0067] FIG.5 depicts the NMR results for Example 10 (H-006-149). NMR Recorded on a 400 MHz nuclear magnetic resonance spectrometer (mr400 instrument; 399.979 MHz,
1H NMR spectrum, 1D in D
2O; reference to external acetone @ 2.225 ppm; temp.25.9 ºC.; actual temp = 27.0 ºC.; oneNMR probe). [0068] FIG.6 depicts the NMR results for Example 11 (H-006-145). NMR Recorded on a 400 MHz nuclear magnetic resonance spectrometer (mr400 instrument; 399.979 MHz, 1H NMR spectrum, 1D in D
2O; reference to external acetone @ 2.225 ppm; temp.25.9 ºC.; actual temp = 27.0 ºC.; oneNMR probe). [0069] FIGS.7A and 7B depict the NMR results for Example 12 (H-006-152). NMR Recorded on a 400 MHz nuclear magnetic resonance spectrometer (mr400 instrument; 399.979 MHz, 1H NMR spectrum, 1D in D
2O; reference to external acetone @ 2.225 ppm; temp.25.9 ºC.; actual temp = 27.0 ºC.; oneNMR probe). DETAILED DESCRIPTION
[0070] Creating new means of enhancing the formation of water-soluble complexes of drug compounds that may or may not have poor water solubility for cannabinoids and endocannabinoids and combinations of the same continue to be needed. However making complexes with such drugs that may have poor or limited water solubility can result in inadequate oral delivery due to unacceptable taste or consistency, and can have significant ramifications in many fields including pharmacology, animal care, food supplements, animal feed, and the like. The complexes formed using the methods herein can assist compounding pharmacies in formulating patient-specific amounts of an active compound as well as formulating the active compound into palatable formulations for pediatric patients. Without being limited to any theory, the proposed sugar-drug combinations may be created by hydrogen bonding or by host–guest chemistry forming a complex between one or more non-nutritive sugars and the drug compound, wherein two compounds are in a complex and one chemical compound has a cavity into which a "guest" compound can be accommodated. The interaction between the host and guest in a complex can include hydrophobic interactions such as van der Waals interactions. Nevertheless, in this water-soluble complex, the drug compound’s solubility in water increases as compared to the solubility of the drug compound when not in the form of a complex with a non-nutritive sugar. [0071] In complexes formed between a surfactant and a drug compound and optionally a non-nutritive sugar, different chemical interactions forming a complex may occur. However, it is a complex that is formed, rather than a mixture of compounds remaining as separate molecules in the solvent. [0072] The water-soluble complexes described herein can also impart a sweeter taste, instead of a bitter or acrid taste imparted by many drug compounds in free form or salt forms. As mentioned elsewhere herein, salt forms of a compound may be less preferred as the salt may occupy positions normally taken by hydrogen bonds when forming the complex when using a non-nutritive sugar alone. Salt forms of a drug compound with a surfactant without a non- nutritive sugar do have the same issue. The sweeter taste arising from a non-nutritive sugar being in the complex will be of benefit when administering compounds to pets, and geriatric and pediatric patients by contributing the sweeter and more palatable taste. [0073] Methods are provided for creating new means of enhancing the formation of water-soluble complexes of cannabinoid/endocannabinoid compounds or various combinations thereof. The drug compounds (e.g., cannabinoid compounds, endocannabinoid compounds, and combinations thereof) may have poor or insufficient water solubility or, for example, be inadequate for oral delivery due to unacceptable taste or consistency. The ability
to make water-soluble complexes comprising such drug compounds has significant ramifications in many fields including pharmacology and animal care. The complexes formed using the methods described herein can assist in formulating subject-specific amounts of an active drug compound as well as formulating the active compound(s) into palatable formulations for pediatric or elderly patients as well as animals. While the water-soluble complexes may require pharmaceutical acids and/or various surfactants added to produce the water-soluble complex, that is all the water-soluble complex requires. The water-soluble complex can then be used to prepare pharmaceutical compositions having additional components such as carriers, excipients, stabilizers, and the like, but these additional components are not integrated into the water-soluble complex. Thus, while the optional presence of a non-nutritive sugar may impart an improved taste, in complexes having one or more non-nutritive sugars, said sugar is not present as a sweetener, but rather to form the water- soluble complex either with the compound alone or in combination with the compound and surfactant thereby causing the drug compound to have improved water solubility over that of the compound when not in a complex produced by the methods discussed herein and measured at 20 ̊C. [0074] The contemplated water-soluble non-nutritive sugar-drug complex also may improve the amount of drug compound delivered (C
max) and alter the pharmacokinetics of the cannabinoid or endocannabinoid from that of the drug compound when not complexed with the non-nutritive sugar and/or surfactant. The complexed sugar-drug compound also seems to be protected from harsh stomach acids. For some of the water-soluble complex containing the endocannabinoid or cannabinoid drug compound, and without being bound to theory, the dose amount of the drug compound in the water-soluble complex may need to be decreased relative to the drug compound that is not in the water-soluble complexed given changes in the pharmacokinetics when in the water-soluble complex. [0075] 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 or altered pharmacokinetic attributes, improved storage 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 complexes formed by the methods described herein should not be considered as a mixture. The method of solubilizing a listed non-nutritive sugar with the compound or the compound and a
surfactant or the surfactant and the compound in a listed solvent or solvent combination can optionally be in the presence of an acid/base/surfactant, followed by drying the solvent after solubilization using the methods described herein (step 1). The dried composition is then dissolved in water forming the water-soluble complex. The dissolved water-soluble complex in water can optionally be filtered and/or dried the complex (step 2). Step 2 can also have the addition of an acid to assist with solubility. Citric acid can be added to a water-soluble complex forming a mixture to provide additional stability benefits for a pharmaceutical composition. The final water-soluble complex yields a new more water-soluble compound in the form of the complex. [0076] The water-soluble complex can then be further mixed with other pharmaceutical excipients, stabilizers, fillers, flavorings, sweeteners, and the like as mentioned herein. After adding one or more of these other pharmaceutical excipients, stabilizers, fillers, flavorings, and sweeteners, the composition is then in the form of a mixture. The water-soluble complex formed by the methods disclosed involves the host-guest chemistry that is not contemplated when forming such mixtures. Stated differently, the degree of water-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 KCl as well as citric acid. [0077] By using a powdered or liquid formulation, dispensing proper doses is easier, reducing errors, variations, and waste based on variations in the pill-splitting technique. Another benefit achieved by the method and products produced by the method is a decreased amount of an active cannabinoid/endocannabinoid compound 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. Additionally, given the improved water-solubility obtained by some of the compounds and their rapid release in a patient, less of the drug compound may be required for use in a dosage form than what would be used for the drug compound if not in the water-soluble complex. Definitions [0078] The following definitions provide guidance on term interpretation unless otherwise indicated by the context in which the term appears elsewhere in the specification. [0079] 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. [0080] 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%. [0081] 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. [0082] 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 a cannabinoid/endocannabinoid. 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. [0083] 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. [0084] The “weight ratio” of a “sugar to a drug compound” when using a non-nutrtive sugar in the water-soluble complex may range from about 1:1 to 20:1, and any 0.1 value between. [0085] The “molar ratio” of a “sugar to a drug compound” (wherein the “drug compound” or “compound” is intended to mean a cannabinoid and endocannabinoid or a combination of cannabinoids or endocannabinoids) in a complex may range from about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, and 9:1 to about 10:1 of non-nutritive sugar to drug or surfactant to drug and any 0.1 value between.
[0086] The use of the term “sugar” and “non-nutritive sugar” means a non-nutritive sweetener. A non-nutritive sugar can be rubusoside, dulcoside B (also known as rebaudioside C), stevia, rebaudioside A (also known as stevioside A3), stevioside (also known as diterpene glycoside and has a chemical formula of C
38H
60O
18), n-octyl glucose, n-dodecyl-β-D-maltoside (also known as dodecyl maltoside or lauryl maltoside), stevia (has a chemical formula of C
44H
70O
23), a steviol glycoside such as that derived from Stevia rebaudiana, ADVANTAME®, NEOTAME®, thaumatin, saccharin, sucralose, a steviol glycoside, Lou Han Guo, aspartame, acesulfame potassium, or allulose. While other diterpene glycoside-like sugars are known, in certain embodiments, only those that are FDA GRAS-approved are contemplated for use in creating water-soluble complexes like with other non-nutritive FDA GRAS-approved sugars. Preferably, the non-nutritive sugar is one or more of rubusoside, stevia, dulcoside B, stevioside, n-dodecyl-β-D-maltoside, or rebaudioside A which can be used in any combination or permutation (e.g., a combination of stevioside and rubusoside). Also contemplated is any permutation or combination of one or more of the listed non-nutritive sugars (2 of the non- nutritive sugars, 3 of the non-nutritive sugars, etc.). The price of a non-nutritive sugar is also a factor in whether a sugar is commercially a good sugar for solubilizing the drug compound. Exemplary sugars for making the “sugar-drug compound” are rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, rebaudioside A, rebaudioside B, rebaudioside D, stevioside, stevia n-octyl glucose, or n-dodecyl-β-D-maltoside. Not to being bound by a theory, it is believed that upon aggregation (e.g., complexation) of the non-nutritive sugar with the drug compound, a stable complex occurs, presumably by non-covalent hydrogen bonding and optionally hydrophobic-hydrophobic interactions, such as van der Waal forces. [0087] Additional contemplated non-nutritive sugars to the diterpene glycosides for complexation with the drug compounds include: ADVANTAME® – is an aspartame analog; N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-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 a spike in insulin. 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. 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.
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. Sucralose – sold under the name Splenda and is an organochlorine sweetener having the chemical name of 1,6-dichloro-1,6-dideoxy-β-D-fructofuranosyl-4-chloro-4- deoxy-α-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. 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. 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. 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. 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. [0088] 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:
[0089] By a “compound”, “drug compound”, and “poorly soluble drug” are meant cannabinoids or endocannabinoids, or a combination thereof. The cannabinoid or endocannabinoid may or may not be poorly soluble. The drug compound can include more than one active drug compound in a complex. The terms also include the salt form, free form, polymorphy, solvate, or co-crystal of the endocannabinoid or cannabinoid. [0090] The term “insoluble” is often applied in the art to poorly or very poorly soluble compounds (see e.g., Savjani et al. “Drug Solubility: Importance and Enhancement Techniques,” ISRN Pharm. 2012, doi: 10.5402/2012/195727). A “poorly soluble” drug compound can be a compound that can dissolve at no more than about 100 mg per milliliter, and likely less than 50 mg per milliliter of compound. Generally, a poorly soluble compound is considered “poorly soluble” in water at 20 ºC when less than about 1 mg/mL of the compound is made soluble over the physiological pH range (see e.g., C. Moreton, “Poor Solubility – Where do we stand 25 years after the ‘Rule of Five’?” Amer. Pharm. Rev. (2021). [0091] As used herein, a “sugar-drug compound” and “hydrogen-bonded sugar-drug compound” can also be terms to describe a complex between a non-nutritive sugar and a drug compound. The water-soluble complex can also be formed between a non-nutritive sugar, a compound, and a surfactant. The drug compound may or may not be a poorly soluble compound. The drug compound should have available hydrogen bonding sites to form such bonds with a non-nutritive sugar. The term “water-soluble complex”, “water-soluble cannabinoid/endocannabinoid complex”, and “complex” are used used interchangeably and are intended to be equivalents to include any and all similar descriptions (including those having a
non-nutritive sugar and drug, a surfactant and drug, or a surfactant, drug and non-nutritive sugar) provided herein as well as in the priority application(s) to which this application claims the benefit, including, without limitation, the terms “an inclusion complex” and “complex”. Each of these refers to a stable product formed as described herein between a non-nutritive sugar and a compound, a surfactant and drug compound, or a surfactant, drug compound, and non-nutritive sugar produced by the methods described herein The compound can be a cannabinoid, endocannabinoid, or combination of cannabinoids and endocannabinoids. [0092] A sugar as indicated herein for creating a water-soluble complex is a nonnutritive sugar and maybe a diterpene glycoside (DTG) or any of the other non-nutritive sugars listed herein. The drug compound is indicated in formulas as “Drug,” as set forth in the following formula (Formula I): [ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^]
^^^^ ^^^^ ^^^^ ^^^^ ^^^^ or as (Formula II): [ ^^^^ ^^^^ ^^^^]
^^^^ ^^^^ ^^^^ ^^^^ ^^^^ and other such formulas disclosed herein. The non-nutritive sugar is in a complex with the drug compound. In both formulae, “p” is an integer from about 1 to about 12.0 or up to about 20.0. Without being bound by theory, the non-nutritive sugar-drug compound can have hydrogen bonds created between the non-nutritive sugar and the drug compound and/or maybe in the form of a complex.
[0093] A “stable” water-soluble complex comprising a sugar-drug compound is (i.e., [ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^] ^^^^ ^^^^ ^^^^ ^^^^ ^^^^) 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., efficacious administration to a subject). By way of example only, a water-soluble complex as described herein is deemed stable if the complex remains intact in water at pH 8.5 for at least 2 hours. Alternatively, or additionally, the water-soluble sugar-drug complex is deemed stable if it remains intact in water at pH 4 for at least 2 hours. Alternatively, or additionally, the water-soluble complex is deemed stable if it remains intact at 30 °C for at least 90 days when dried to a powder. Accordingly, in a preferred embodiment, when a complex as described herein meets any of these stability tests, that complex is deemed to be a stable complex. [0094] A “stable” water-soluble complex, such as those described herein, and made by the methods described herein are those 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). [0095] A water-soluble complex further comprising a nonionic solvent, wherein the
nonionic solvent is a polysorbate (PSS) and is reflected in formula (III): [ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^] ^^^^[ ^^^^ ^^^^ ^^^^] ^^^^[ ^^^^ ^^^^ ^^^^ ^^^^]). Said sugar/surfactant/drug complex is prepared by the methods described herein. “p” is the ratio of sugar to drug compound and
is the ratio of PSS to drug compound. The PSS-containing water-soluble complex remains 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). [0096] A “water-soluble complex comprising a poloxamer surfactant is reflected in
formula (IV): [ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ] ^^^^ [ ^^^^ ^^^^ ^^^^ ] ^^^^[ ^^^^ ^^^^ ^^^^ ^^^^]) 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 drug compound for the purposes described herein (e.g., therapeutic administration to a subject). “p” is the ratio of non-nutritive sugar to drug compound and
is the ratio of PSS to drug compound. [0097] By “a cannabinoid” is meant to include a drug compound that is either synthetically made or can be derived from a plant such as C. sativa or another cannabinoid- containing plant. The term also includes solvates, cocrystals, and polymorphs of a cannabinoid. The term as used herein is also meant to include an endocannabinoid or an endocannabinoid solvate, polymorphy, or cocrystal unless the term endocannabinoid is used separately from the term cannabinoid. For example, Tuber elanosporum (the black truffle) contains anandamide. In addition to C. sativa are other hemp plant species that produce various cannabinoids, including C. indica and C. rudereralis. Cannabinoids include for example cannabicyclols, cannabichromenes, cannabielsoins, cannabitriols, cannabidiols, cannabigerols, cannabinols, cannabinodiols, delta-tetrahydrocannabinols, and delta-tetrahydrocannabinols. An exemplary group of cannabinoids includes delta-8-tetrahydrocannabinol (Δ8-THC), delta-8- tetrahydrocannabinolic acid (Δ8-THCA), delta-9-tetrahydrocannabinol (Δ9-THC or THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), and tetrahydrocannabinolic acid (THCA), cannabiidiolic acid (CBDA). Cannabinoids can derive from hemp plants, but can also derive from other plants that produce cannabinoids. Additional cannabinoids contemplated for use in the water-soluble complexes described herein include cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabicyclovarin (CBLV), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), cannabichromenic acid (CVCA), cannabichromevarin (CBCV), cannabielsoin (CBE), cannabielsoin acid A (CBEA- A), cannabielsoin acid B (CBEA-B), 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-dihydroxy-delta-6a-tetrahydrocannabinol, cannabitriol (CBT), cannabitriolvarin (CBTV),
cannabidiol monomethylether (CBDM), cannabidivarinic acid (CVDVA) cannabidiorcol (CBD-C1), cannabidivarin (CBDV), cannabidiphorol (CBDP), cannabnigerol (CBG), Cannabigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabigerol monomethylether (CBGM), cannabigerolic acid monomethylether (CBGAM), cannabigerolic acid (CBGA), cannabinolic acid (CBNA), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabinol (CBN), cannabiorcool (CBN-C1), cannabivarin (CBV), cannabinol methylether (CBNM), cannabinol-C2 (CBN-C2), cannabinol-C4 (CBN-C4), delta-9-tetrahydrocannabinol- C4 (THC-C4), delta-9-tetrahydrocannabiorcol (THC-C1), delta-9-tetrahydrocannabiorcolic acid (THCA-C1), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-9- tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabivarinic acid (THCVA), delta-9- tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabiphorol (THCP), 10-oxo-delta-6a-tetrahydrocannabinol (OTHC), cannabichromanon (CBCF), cannabifuran (CBF), cannabiglendol, Delta-9-cis- tetrahydrocannabinol (cis-THC), cannabicitran (CBT), dehydrocannabifuran (DCBF), Tryhydroxy-delta-9-tetrahydrocannabinol (triOH-THC), and cannabiripsol (CBR). In certain embodiments, the drug compound is a soluble cannabis terpene. [0098] By “a cannabis terpene” is meant a terpene that is naturally occurring in a cannabis plant strain (e.g., Cannabis indica, Cannabis sativa, or Cannabis ruderalis), however, the cannabis terpene can also be synthetically manufactured. Terpenes are the primary constituents of essential oils and contribute to or are responsible for various properties including an aroma and/or a flavor of a cannabis plant strain. It is speculated that certain cannabis terpenes may have synergistic effects with cannabinoids. See, e.g., Sommano et al., (2020) “The Cannabis Terpenes,” Molecules.25(24): 5792. Cannabis terpenes include but are not limited to β-pinene, α-pinene, limonene, terpinolene, β-caryophyllene, and β-myrcene. Terpenes are highly non-polar and are insoluble in water. Nanoemulsions of terpene-rich by- products have been reported. See, e.g., Tao, et al., (2023) “Nanoemulsions of terpene by- products from cannabidiol production have promising insecticidal effect on Callosobruchus maculatus,” Heliyon 9(4), e15101. It is contemplated that cannabis terpenes can be prepared as a water-soluble complex by the methods disclosed herein. In an embodiment, the drug compound used in the complexes and methods described herein can be a cannabis terpene. It is contemplated that a water-soluble complex having a cannabis terpene will provide improved bioavailability of the cannabis terpene compared, for instance, to an emulsion or nanoemulsion of cannabis terpene not in the form of a water-soluble complex. [0099] By “treatment” and “treating” are meant the use of the complexes and
formulations comprising the same as described herein to treat a subject for a particular condition or disease. A “subject” can be an animal such as a domesticated animal (e.g., cat or dog), primates, and humans. A subject can be treated for an endocannabinoid deficiency (CED) using cannabinoid supplements formulated as a water-soluble complex. Endocannabinoid deficiencies and disorders can include fibromyalgia, irritable bowel syndrome, diabetes, Parkinson’s disease, multiple sclerosis, and Huntington’s chorea (Ritter et al., “Cannabis, One Health, and Veterinary Medicine: Cannabinoids’ Role in Public Health, Food Safety, and Translational Medicine, Rambam Maimonides Medical Journal 11(1): 1-20, 2020). Cannabinoids can also be used to treat certain conditions, for example, CBD has been administered to cats and dogs for treating such conditions as osteoarthritis, seizures, conditions arising from cancer treatment, and anxiety. Cannabinoid compounds have been seen to provide pain reduction in animals and aid with sleep. See e.g., Alvarenga et al., “Scientific Validation of Cannabidiol for Management of Dog and Cat Diseases,” Ann. Rev. Animal Biosci.11: 227- 46 (2023). CBD is one of approximately 125 cannabinoids known to be present in the Cannabis sativa plant and is non-psychoactive. CBD functions through the CB2 receptors. It has been reported in one study that the oral dose of 200 mg per day of CBD for 10 weeks is safe without any adverse effects (Khalsa et al., 2022). Dronabinol and nabilone are FDA- approved cannabinoids for use in treating nausea and vomiting resulting from chemotherapy and who have not responded to antiemetic therapy. Cannabinoids have also been used to alleviate pain in cancer patients (Dariš et al, “Cannabinoids in cancer treatment: Therapeutic potential and legislation,” Bosn. J. Basic Med. Sci. 19(1): 14-23, 2019). Some research suggests that there may also be some anti-tumor activity resulting from certain cannabinoids themselves (Dariš et al, 2019). [00100] Delta-9-tetrahydrocannabinol (Δ9-THC) is the most psychoactive component in the C. sativa plant. One form of THC, nabilone, has been linked to improved motor scores when administered to Huntington’s chorea patients when the patient was assessed using the Unified Huntington’s Disease Rating Scale (UHDRS) and for dystonia (Khalsa et al., 2022). Nabilone may be effective for treating agitation in patients with Alzheimer’s Disease (AD) (Khalsa et al., 2022). [0101] In addition to plant-derived and synthetic cannabinoids, endogenous cannabinoids are also included in the genus of compounds contemplated for complexation with a sugar or with a surfactant alone or in combination with a non-nutritive sugar. A non-nutritive sugar can also be complexed alone with a cannabinoid/endocannabinoid. Endocannabinoids target various internal receptors as discussed in Duncan et al., “Cannabinoids and
endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies,” Neural. Regen. Res.19(4): 788-99, 2024.
See Khalsa et al., (2022); Legare et al., “Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals,” Pharmacology 107(3-4): 131-49; Lindner et al.,
“Therapeutic Potential of Cannabinoids in Glaucoma,” Pharmaceuticals (Basel) 16(18): 1149, 2023. [0102] It is noted that various polymorphs of cannabinoids have been described via X- ray crystallography such as delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9- tetrahydrocannabinolic acid B (THCA-B), cannabidiol (CBD), cannabinol (CBN), and cannabigerol (CBG) as discussed in Filer, “Cannabinoid crystal polymorphism,” J. Cannabis Res.4: 23, 2022. Some believe that the activity of CBD may be based on the length differences of the alkyl chain located at the C-5’ position, making it of interest to find homologs (Straker et al., “Polymorph prediction through observed structural isomorphism leading to a new crystalline form of cannabidiol,” CrystEngComm 25: 2479-84, 2023). It is also known that CBD for example has poor water solubility and also inconsistent bioavailability (Hossain et al., “Current Challenges and Opportunities for Improved Cannabidiol Solubility, Int’l J. Mol. Sci.24: 14514, 2023. Cocrystals of cannabinoids are also known and described such as in WO 2020/089424 and Filer, “Cannabinoids as Cocrystals,” Med. Cannabis Cannabinoids 5(1): 7- 8, 2022. [0103] The method of preparing the water-soluble complex comprising a drug compound (cannabinoid or endocannabinoid) involves dissolving a drug compound in ethanol (or another solvent) in the presence of a surfactant and optionally in the presence of a non- nutritive sugar. A method of making the complexes without a surfactant and only with a non- nutritive sugar generally is lesspreferred. Once the drug compound, surfactant, and optional sugar are dissolved in a solvent (or solvent combination), the solvent is removed by drying or evaporating (e.g., freeze-drying or lyophilizing or other means of evaporating the ethanol from the mixture) the liquid from the composition. Optionally, the first dissolving step may further involve the use of one or more pharmaceutically acceptable acids to assist with the dissolution of the compounds. The dried components are then dissolved in water evidencing that a water- soluble form is created. The second step of dissolving in water can be done in the further presence of a pharmaceutically acceptable acid and/or heating. [0104] The water-soluble sugar-compound complex formed by this method can then be formulated into a solid form for oral, sublingual, and/or buccal administration, such as a pill, capsule, caplet, chewable (e.g., a gummy), tablet, a lozenge, and/or a soft gel. Formation of such pills, capsules, lozenges, oils, tinctures, etc. can then have or include stabilizers, other excipients, flavorings, colors, carriers, etc. added, but these additional compounds are not integrated into the water-soluble complex. The water-soluble sugar-compound complex can also, or alternatively, be formulated into a suppository, lotion, gel, and/or ointment. The water-
soluble complex can also be formulated as an inhalable powder. The water-soluble complex can be formulated into a suitable topical form. In another aspect, the water-soluble complex can be formulated into an injectable liquid for injection into a subject subcutaneously (SC), intravenously (IV), intraperitoneal (IP), and intramuscularly (IM). [0105] These various formulations are expected to offer different pharmacokinetics that may be beneficial depending on the condition being treated. 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 or other form to the subject. Additionally, or alternatively, a lyophilized water-soluble complex can be formulated as a food additive or as an additive into an animal feed. The drug compound 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 the surfactant and optionally a non- nutritive sugar. Preferably, the drug compound and sugar optionally having a pharmaceutically acceptable acid are 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. The one or more solvents used in the first step in forming the water-soluble complex 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 1:0.00005 of ethanol to 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). [0106] 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 compound in the complex formed by the method. Preferably, the acid or base is a pharmaceutically acceptable acid or base when used with the drug compound. The acid or base can be added until solubility is achieved for the drug compound and the non- nutritive sugar.
[0107] 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 non-nutritive sugar. Cannabinoids contemplated include those drugs that are insoluble, have limited solubility, and are soluble in water. A cannabinoid (or endocannabinoid) 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 surfactant and optional non-nutritive sugar (or drug compound and sugar alone) 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, surfactant, and optional non-nutritive sugar, and optionally in the further presence of an acid/base to further solubilize and form the water-soluble complex. Optionally, the water-soluble complex remains soluble in water without the formation of a precipitate for at least 24 hours. 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. [0108] Other pharmaceutically acceptable solvents that can be used alone or in combination to form the water-soluble complex as the first solvent. In one aspect, the solvent can be used alone to dissolve the components forming the water-soluble complex. In another aspect, two or more solvents may be used, wherein one solvent dissolves the cannabinoid/endocannabinoid and another solvent dissolves that surfactant, and then the two dissolved compositions are combined and dried. Additional solvents contemplated in this matter 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-1-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, tetrahydrofuran, 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, tetrahydrofuran, 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, isopropyl acetate, methylacetate, 3-methyl-1-butanol, methylethylketone, 2- methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine. [0109] The surfactants contemplated for making the water-soluble cannabinoid/endocannabinoid complex can be a nonionic surfactant such as 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) 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®. [0110] In addition to nonionic surfactants for use in forming the water-soluble complexes described herein, also contemplated are ionic surfactants. One example of an ionic surfactant is DATEM (diacetyl tartaric ester of mono- and di-glycerides). [0111] If desired, a polyethylene glycol (PEG) can be optionally added to the liquid and powdered formulations to further improve bioavailability after the formation of the water- soluble complex. The PEG generally would be added after step 1, and likely after step 2 of the methods described herein. The molecular weight of the PEG used for these complexes, typically lies 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 mole ratio of PEG to a drug compound may range between and including 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1. In one embodiment, the weight ratio is about 8:1. [0112] For administration, the powdered water-soluble cannabinoid/endocannabinoid 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 a nutrition drink, energy drink, or an electrolyte-rich drink. For example, the drug compound in the water-soluble complex now 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.), or oral routes (oral to enter the gastrointestinal tract or for buccal or sublingual administration). Oral routes include sublingual for faster absorption through the mucous membranes of the mouth. The water-soluble complex can also be formulated into a metered nasal spray or delivered by subcutaneous or intramuscular injection. [0113] For veterinary use, the formulations comprising the water-soluble complex may be administered in forms such as in animal feed, solution, drop, or chewable. The drug compound in the water-soluble complex now having improved water solubility can also be added directly to drinking water. [0114] 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, corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, and hypromellose. Additional compounds that can be combined with the water-soluble complex include formers, oral stool softeners, oral stimulants, and/or rectal suppositories, however, in this form, they are mixtures comprising the complex and the one or more compounds that have been added. [0115] 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 water-soluble 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 water-soluble complexes in a gelative capsule, placing the complexes into an insoluble matrix (e.g., Slow-K or Imdur Durules), placing the complexes into an eroding matrix (e.g., MST Continus, Phyllocontin Continus), and/or enclosing the complexes 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 water- soluble complex allows at least a twofold reduction in dosage frequency as compared to that drug compound when not in the form of the water-soluble complex. 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 water-soluble complex dosage form releases a discrete portion or discrete portions of the drug compound 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 non-steroidal anti-inflammatory drug (NSAID) products). Another modified-release oral form of the water-soluble complex contemplated is a targeted-release drug product. A water-soluble complex dosage form that releases the drug compound at and/or near the intended physiologic site of action or when administered systemically is released over time. Another modified-release oral dosage of the water-soluble complex is orally disintegrating tablets (ODT), gummy, thin film, or equivalent for sublingual use which allow for passage of the water-soluble complex through the mucous membranes of the mouth for immediate delivery into a subject’s system. If necessary, similar compositions can be created for delivery to other mucous membranes, such as via suppositories. 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. [0116] Water-soluble complexes that have been prepared according to the methods described herein can be packaged in a kit, either separately in individual vessels, or in admixtures with each other for use by an end user (doctor, medical personnel, or patient in need thereof). 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. Alternatively, the water-soluble complexes can be formulated into pre-filled injectable devices, such as pens, or allow a person to formulate for purposes of injection. [0117] The term “pharmaceutically acceptable salt” generally refers to a salt (including an inner salt such as a zwitterion) that possesses effectiveness similar to the free form of the drug compound and which is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). The term “salt(s)”, as employed herein, denotes any of the following: acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. The drug compound to be complexed with a surfactant and/or a non-nutritive sugar can be in the salt form of a cannabinoid compound or the free form of the compound. A salt form of a drug compound salt can allow for the salt component to occupy a binding site on the non-nutritive sugar, so if a compound lacks adequate bonding sites, it can be important to use a free form to form the non-nutritive sugar-drug
complex. [0118] By “a pharmaceutically acceptable acid” 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 acid as used in the methods described herein is to improve the solubility of the drug compound with the surfactant and optional non-nutritive sugar (or drug compound and non-nutritive sugar). Pharmaceutically acceptable acids include 1-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; dodecylsulfuric 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/Zürich:Wiley-VCH/VHCA, 2002. [0119] Examples of bases including pharmaceutically acceptable bases that can be used to solubilize the drug compound during step 1 of the method include sodium hydroxide, zinc hydroxide, calcium carbonate, potassium hydroxide, lithium hydroxide, rubidium hydroxide, magnesium hydroxide, barium hydroxide, calcium hydroxide, strontium hydroxide, and potassium oxide. Other bases include trimethylamine, methylamine, aniline, and pyridine. Buffers can also be used instead of an acid or base to solubilize the compound and sugar. Exemplary buffers include a bicarbonate solution, a carbonate solution, and sodium phosphate (pKa 2.1, 7.2, and 12.3). [0120] By “a pharmaceutically acceptable composition” and “pharmaceutical composition” are meant a composition comprising the water-soluble complex described herein that may be later mixed to further contain one or more of a pharmaceutically acceptable carrier, filler, 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 sweetener for the specific use as a flavoring or additive. The composition can be a solid or a liquid form. A pharmaceutical composition can also include more than one drug compound, e.g., CBD and THC in a certain ratio. While the pharmaceutical composition may contain these components, the components are not part of the water-soluble sugar drug complex. [0121] For embodiments of the method described herein to create a water-soluble complex of a drug compound and surfactant and optionally a non-nutritive sugar (or a drug compound and a non-nutritive sugar), the method includes solubilizing a drug compound, the surfactant, and optional non-nutritive sugar (or only the non-nutritive sugar and drug compound), and changing thepH to about 2.0 to about 12.0 as needed for solubilization using a pharmaceutically acceptable acid or a base. The pH can be adjusted to any 0.1 value between 2.0 to 12.0 as needed for solubilization. The pH can also be adjusted within these ranges when forming a water-soluble complex of a cannabinoid/endocannabinoid and a surfactant and optionally a non-nutritive sugar as well as a water-soluble complex of a cannabinoid/endocannabinoid and a non-nutritive sugar at the step of dissolving the dried drug compound/surfactant/non-nutritive sugar in water. [0122] For embodiments of the method described herein to solubilize a compound or sugar, the temperature of the compound, sugar, and solute can range from about 15 ºC to about 60 ºC, generally about 5 ºC to about 10 ºC from room temperature. An exemplary temperature range is between about 20 and about 30 ºC. [0123] By “improved solubility” of a drug compound is meant an improvement of a drug compound’s water solubility at 20-25 ºC and at physiological pH, when in the form of a water-soluble complex versus the drug compound alone. The drug compound can be insoluble, poorly soluble, etc. Contemplated herein is the complexation and improved solubility of a slightly soluble compound (i.e., less than 10 mg/mL solubility in water at 20-25 ºC and physiological pH) for which the methods described herein improve the compound’s solubility by forming a complex. Solvents can include methanol at 80% methanol, or at 95% (ACS grade) or greater (to 100% methanol) as well as combinations of methanol and ethanol or methanol and water. Solvents can include other solvents listed herein and solvent combinations, such as hexane or chloroform. The drug compound can be dissolved in one solvent and the non-nutritive sugar and/or surfactant can be dissolved in a different solvent, and then the dissolved drug and surfactant/sugar can be mixed. After solubilizing the non- nutritive sugar and/or surfactant and the drug compound in the solvent(s), the solvent(s) is evaporated for example under a high rotary vacuum. Drying proceeds until there is no further
change in the weight of the compounds. The powder resulting from the evaporation step is then resolubilized (dissolved) in water thereby demonstrating the formation of the water- soluble complex. As above, improvements in water solubility are measured at about 20-25 ºC at physiological pH. [0124] By “water-soluble complex”, “water-soluble drug complex,” “water-soluble cannabinoid/endocannabinoid complex”, and “water-soluble complex” are meant to include one or more cannabinoids/endocannabinoids, a surfactant, and an optional non-nutritive sugar (e.g., rubusoside, stevia, dulcoside B, stevioside, n-dodecyl-β-D-maltoside, or rebaudioside A) that through dissolution with a solvent and optionally with a pharmaceutically acceptable acid assists in creating a complex, wherein when the dried form of these components after step 1 are dissolved in water are then found to be water-soluble or have improved water solubility over the drug compound or combination of drug compounds when not in the form of a complex. The terms also include the drug compound and a non-nutritive sugar, although such combinations may have limited solubility. The cannabinoid/endocannabinoid drug compound must be one that can be solubilized fully or partially in a pharmaceutical solvent. The solvent can be 95% ethanol or 100% ethanol (absolute ethanol), an aqueous ethanol solution of 50% ethanol or methanol or greater (50%, 55%, 60%, 70%, 80%, 85% 90%, 91%, 92%, 93%, 94%, 95% spectrophotometric grade ethanol or absolute ethanol) or any combination of the solvents listed herein. Preferably the solvent can dissolve the drug compound and the surfactant and optional non-nutritive sugar. In some cases, the drug compound and the surfactant may be dissolved in two different solvents before mixing together. The dissolved components are then dried to remove the one or more solvents. In step 2, the dried composition is then dissolved in water optionally in the presence of an acid/base or heating. The water-soluble complex when dissolved in water can be optionally filtered to remove any particulates using membrane and methods that are pharmaceutically acceptable. The dissolved water-soluble complex can further be dried and reformulated as discussed herein. The cannabinoid or endocannabinoid compound can be the salt form, acid form, or base form of the compound as well as a polymorph, solvate, or co-crystal. The terms “water-soluble drug complex,” “water-soluble cannabinoid/endocannabinoid complex”, and “water-soluble complex” encompass one or more cannabinoids and/or endocannabinoids in a complex with a surfactant and optional non- nutritive sugar or in a complex with a non-nutritive sugar. [0125] The use of the terms “sugar” and “non-nutritive sugar” means that the sugar is a non-nutritive sweetener. In one aspected, the non-nutritive sugars contemplated for use to form a complex include one or more of rubusoside, dulcoside A, dulcoside B (also known as
rebaudioside C), sucrose, stevia, D-fructose, sucralose, rebaudioside A (also known as stevioside A3), rebaudioside B, rebaudioside D, stevioside (has a chemical formula of C
38H
60O
18), n-octyl glucose, n-dodecyl-β-D-maltoside (also known as dodecyl maltoside or lauryl maltoside), stevia (has a chemical formula of C
44H
70O
23), a steviol glycoside such as that derived from Stevia rebaudiana and n-octyl glucose. Other steviol glycosides contemplated for use in hydrogen bonding and/or drug/compound complex include rebaudioside E, rebaudioside F, and steviolbioside. Additional non-nutritive sugars are listed herein and can be used as well. [0126] The method of improving the water solubility of a compound in certain embodiments involves taking the drug compound and dissolving it in a solvent, e.g., in about 70% to 95% ethanol in the presence of the one or more non-nutritive sugars and or surfactants. The drug compound-to-sugar weight ratio in complexes utilizing a non-nutritive sugar in the complex can be from about 0.1:1.0 to about 1.0:1.0, from 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 to about 20.0. [0127] 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 pills, capsules, tablets, or other formulations are used. A dosage of a formulation of the water-soluble complex comprising the drug compound 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/diterpene glycoside sugar used as the non-nutritive sugar, a dosage would provide no more than about 10 mg/kg of the steviol sugar, because more than that for an average human male of 70 kg, would result in a dosage of 700 mg of the non-nutritive 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. [0128] Another characteristic that may be imparted by the method of improving a cannabinoid/endocannabinoid compound’s solubility is that the storage stability of the drug compound when in the form of the water-soluble complex can be increased over the solubility of the drug compound, not in the complex. [0129] The water-soluble cannabinoid/endocannabinoid complex can be admixed with a pharmaceutically acceptable carrier preparation forming a composition or mixture. A pharmaceutically acceptable carrier for parenteral 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. 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. [0130] The water-soluble cannabinoid/endocannabinoid 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 that can be used with the formed water-soluble complexes 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. [0131] The water-soluble cannabinoid/endocannabinoid complex can optionally include a preservative and/or an additive. Preservatives and additives contemplated for use with the water-soluble complex can be mixed with other compounds as a formulation including antimicrobials, anti-oxidants, chelating agents, inert gases, and the like. The preservative and/or additive is mixed with the water-soluble complex after the formation of the water- soluble-cannabinoid/endocannabinoid complex. However, it is to be remembered that the preservatives and additives are not integral to the formed water-soluble complex, but instead form a mixture with the complex. [0132] A water-soluble complex of a surfactant and optional non-nutritive sugar or a non-nutritive sugar with a cannabinoid/endocannabinoid can be used to treat subjects having a wide range of clinical conditions including but not limited to nausea and vomiting, anorexia, appetite stimulation, sleep apnea, dystonia, conditions related to Parkinson’s disease (PD), conditions related to Alzheimer’s disease (AD), agitation associated with AD, multiple sclerosis (MS) associated spasticity, and post-traumatic-stress-disorder (PTSD) (Khalsa et al., “Review: Cannabinoids as Medicinals,” Curr. Addict. Rep.9(4): 630-46, 2022). [0133] The above disclosure generally describes the materials and methods for making drug compounds more soluble through complex formation with a surfactant and optional non- nutritive sugar or a non-nutritive sugar, and, in some cases, to make a compound more palatable to a patient and/or animal. 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 not intended to limit the scope of the methods and compositions described herein. The amounts of the non-nutritive sugar(s) 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. EXAMPLES [0134] In all the following examples, the same conditions were used unless otherwise noted. The water used is deionized, distilled water. Unless indicated otherwise, 95% ethanol (ACS spectrophotometric grade, unless otherwise specified) was used. In all cases, high vacuum drying was performed at room temperature. All examples used an Edvards Model RV8 high vacuum pump with an IKA model C-mag HS7 magnetic stirrer. The rotary evaporator used was a Heidolph Basis Hei-VAP value (No.560-00000-01-1). [0135] The materials used were Kolliphor P 188 (Sigma-Aldrich Poloxamer 188, Cat. No. 15759), Tween® 80 (Sigma-Aldrich Cas-No. 9005-65-6, Cat. No. P1754), and Tween® 20 (Sigma-Aldrich Cas No.9005-64-5, Cat No. P1379). CBD Crystal™ containing 99% pure CBD isolate powder that is hemp derived was obtained from CBD Crystal. EXAMPLE 1 – CBD and Stevioside [0136] The following example tested whether or not stevioside improves the solubility of CBD. A mole ratio of 1:10 CBD Crystal™ to stevioside was used in a volume of 2.0 mL 85% ethanol. It is noted that cannabidiol (CBD) has a solubility of only about 0.7 μg/mL in water, which is considered insoluble (insoluble in water is when less than 1 gram in a liter can be dissolved). [0137] Generally, ingredients are deposited into a sealed container with ethanol and vortex-mixed to form a solution (step 1). The solution is subjected to centrifugation. The ethanol (solvent) was evaporated, and the dried mixture dissolved in water (step 2). This mixture is centrifuged again and the supernatant can be filtered through a membrane. The flow-through is dried and can be examined for the formation of the compounded CBD. [0138] The admixing process involved dissolving the CBD and stevioside in 2.0 mL denatured ethanol (85%) at a 1:10 drug-to-sugar ratio while vigorously stirred at room temperature for 30 min at 20 ºC. The reaction appeared hazy. For this example, the process included adjusting the pH using either 0.1 N HCl or 0.1 N citric acid as necessary to try to attain complete dissolution and a clear and homogeneous reaction mixture. [0139] For the experiment using citric acid, the pH was reduced to 3.5 and produced a clear but slightly hazy solution. For the experiment using HCl, the pH was reduced to about 3.0, and the solution was clear and homogeneous; thus HCl appeared to solubilize the
compounds more effectively than citric acid. [0140] Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35
oC. water bath temperature resulting in a white solid. The 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 high vacuum pump with an IKA Model C-MAG HS7 magnetic stirrer. The rotary evaporator used was 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. [0141] For step 2, the dried white solid was dissolved in 2 mL water at room temperature and stirred at ambient temperature. The water was removed over a rotary evaporator using a high vacuum pump at 35
oC. water bath temperature producing a white solid. This white solid was suspended in water for
1H-NMR analysis to assess if the CBD formed a water-soluble complex. [0142] NMR analysis did not detect any CBD peaks, indicating that a water-soluble complex having CBD was not formed using these steps.
sugar, n-Dodecyl β-D-maltoside (DDM), significantly improves the solubility of CBD Crystal™. [0144] Step 1: In an oven-dried single-neck RB flask equipped with a magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD (0.01590 mmol) and 81.2 mg n-dodecyl β- D-maltoside (0.1590 mmol) (molar ratio of 1:10 CBD Crystal™ to DDM) were weighed into the RB flask and dissolved in 2.0 mL denatured ethanol (85%) at ambient temperature. The reaction mixture was vigorously stirred at room temperature for 30 min. The two materials slowly solubilized well in ethanol. The resulting solution was a clear colorless homogenous solution. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. water bath temperature resulting in a white powder, 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. [0145] Step 2: The white powder (1:0:10: molar ratio CBD:DDM) was then dissolved
in deionized water (DI) at room temperature in an RB flask with a magnetic stir bar, and was soluble immediately, forming a clear colorless homogenous solution with lots of frothing. The solution remained unchanged after 30 minutes. The water was removed over a rotary evaporator using a high vacuum pump at 35 ºC. water bath temperature producing a white solid. This white solid was suspended in water for 1H-NMR analysis to assess if compounded CBD was formed. [0146] The NMR analysis confirmed that a water-soluble complex of CBD Crystal™ and DDM had formed as seen in FIG. 1 as indicated by the “A” peaks. These data suggest nearly 100% solubility of CBD Crystal™ in water in the presence of DDM. EXAMPLES 3-13 [0147] In all the following examples, the same conditions were used unless otherwise noted. The water used for the dissolution of materials was deionized water, and the water to prepare the NMR samples was deuterium oxide (D
2O; “heavy water”). Unless indicated otherwise, 85% denatured ethanol CAS# 64-17-5 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 (and other solvents or solvent combinations) 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. water bath temperature to produce the solid. EXAMPLE 3: CBD Crystal™ and Tween® 20 (molar ratio of 1:5 CBD to Tween® 20) [0148] The following example indicates that Tween® 20 (Sigma-Aldrich), a representative polysorbate surfactant, significantly improves the solubility of CBD in water. [0149] Step 1: In an oven-dried single-neck RB flask equipped with a magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD (0.0318 mmol) and 195 mg Tween® 20 (0.1590 mmol) (molar ratio of 1:5 CBD to Tween® 20) were weighed into the RB flask and dissolved in 2.0 mL denatured ethanol (85%) at ambient temperature. Both materials were immediately soluble in ethanol. The reaction mixture was vigorously stirred at room temperature for 30 min. The resulting solution was a clear colorless homogenous solution. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. bath temperature resulting in a sticky liquid. The sticky liquid 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. [0150] Step 2: The dried sticky liquid (1:0:5.0 molar ratio CBD:Tween® 20) was then dissolved in 2 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. The resulting solution (pH~5.5 ± 1) was pale white and homogenous by eye. The solution was not turbid, and there were no solids. A frothing foam formed due to the detergent nature of Tween® 20. The aqueous solution was dried over a rotary evaporator using a high vacuum at 35 °C. bath temperature to get the sticky liquid. The sticky liquid was dried over a high vacuum at room temperature for an additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0151] The resulting sticky liquid was dissolved in 2 mL of heavy water, forming a pale white homogeneous solution, which was analyzed by NMR. [0152] The NMR analysis confirmed that the above method yielded 100% solubility of the CBD Crystal™ and Tween® 20 at the 1:0:5.0 molar ratio; the process produced a CBD:Tween® 20 complex (FIG.2). These data indicate that CBD is soluble in water in the presence of Tween® 20. Notably, the clarity of a solution is not necessarily correlative to the formation of a water-soluble complex having improved solubility. The data in FIG.2 indicates that the CBD Crystal™ formed a complex that was about 100% soluble in water given the “A” peaks and their height in the NMR. The “B” peak(s) represent the Tween® 20. EXAMPLE 4: CBD and Tween® 20 ~ pH 2 (molar ratio of 1:5 CBD Crystal̊ to Tween® 20) [0153] The following example indicates that Tween® 20, a representative polysorbate surfactant, significantly improves the solubility of CBD Crystal™ at acidic pH. [0154] Step 1: In an oven-dried single-neck RB flask equipped with a magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD (0.0318 mmol) and 195 mg Tween® 20 (0.1590 mmol) (molar ratio of 1:5 CBD to Tween® 20) were weighed into the RB flask and dissolved in 2.0 ml denatured ethanol (85%) at ambient temperature. Both materials were immediately soluble in ethanol. The reaction mixture was vigorously stirred at room temperature for 30 min. The resulting solution was a clear colorless homogenous solution. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35
°C. bath temperature resulting in a sticky liquid. The sticky liquid 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. [0155] Step 2: The dried sticky liquid (1:0:5.0 molar ratio CBD Crystal™: Tween® 20) was then dissolved in 2 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. The resulting solution (pH~4.8) was pale white and homogenous by eye. The solution remained pale, white, and homogenous by visual examination after 30 minutes. The pH of the solution was adjusted to pH 2 by the addition of 0.1 N HCl to see if there was an improvement in the complex’s solubility. There was no change in color. A lot of foam was present in the solution. The aqueous solution was dried over a rotary evaporator using a high vacuum at 35 °C. water bath temperature to get the sticky liquid. The sticky liquid was dried over a high vacuum at room temperature for an additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0156] The resulting sticky liquid was dissolved in 2 mL heavy water forming a pale white homogeneous solution, which was analyzed by NMR. [0157] NMR analysis confirmed the 100% solubility of the CBD Crystal™ and Tween® 20 at the 1:0:5.0 molar ratio; the process using Tween® 20 and HCL also produced a CBD-Tween® 20 water-soluble complex. These data indicate that CBD Crystal™ in the complex is rendered soluble in water using this method with the addition of the acid. The method does not require a non-nutritive sugar to make the water-soluble complex that causes the CBD to have increased solubility over the CBD Crystal™ when it is not in the form of a complex. EXAMPLE 5 – CBD Crystal™, Stevioside, and Tween®-20 ~ pH 2 (molar ratio of 1:5:5 CBD to stevioside to Tween® 20) [0158] The following example indicates that Tween® 20 and stevioside, significantly improve the solubility of CBD Crystal™. [0159] Step 1: In an oven-dried single-neck RB flask equipped with a magnetic stir
bar and septa (flask cap), 10 milligrams (mg) CBD Crystal™ (0.0318 mmol), 128 mg stevioside (0.1590), and 195 mg Tween® 20 (0.1590 mmol, Sigma-Aldrich) (molar ratio of 1:5:5 CBD to stevioside to Tween® 20) were weighed into the RB flask and dissolved in 3.0 mL denatured ethanol (85%) at ambient temperature. The reaction mixture was vigorously stirred at room temperature for 30 min. The three materials slowly solubilized well in ethanol. The resulting solution was a clear colorless homogenous solution. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. water bath temperature resulting in a sticky liquid. The sticky liquid 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. [0160] Step 2: The dried sticky liquid (1:0:5.0:5.0 molar ratio CBD Crystal™:stevioside:Tween® 20) was then dissolved in 3.0 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. The solution was a white turbid (~pH 4.8), which remained unchanged after 30 minutes. The pH of the solution was adjusted to pH 2 by the addition of 0.1 N HCl. There was very little to no change in turbidity. The aqueous solution was dried over a high vacuum at room temperature for an additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0161] The resulting sticky liquid was dissolved in 2.0 mL heavy water forming a pale white homogeneous solution, which was then analyzed by NMR. [0162] The NMR analysis confirmed the presence of a water-soluble complex comprising the CBD Crystal™, stevioside, and Tween® 20 at the 1:0:5.0:5.0 molar ratio; the process using Tween® 20, stevioside, and HCl produced a CBD Crystal™: stevioside: Tween® 20 water-soluble complex (FIG. 3). These data indicate that the CBD Crystal™ in the complex was rendered about 100% soluble in water when using the process of this example given the height of the “A” peak. EXAMPLE 6 – CBD Crystal™ and Tween®-80 (molar ratio of 1:5 CBD Crystal™ to Tween® 80)
[0163] The following example indicates that Tween® 80, another representative polysorbate surfactant, significantly improves the water solubility of the CBD Crystal™. [0164] Step 1: In an oven-dried single-neck RB flask equipped with magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD Crystal™ (0.0318 mmol) and 208 mg Tween® 80 (0.1590 mmol, Sigma-Aldrich) (molar ratio of 1:5 CBD to Tween® 80) were weighed into the RB flask and dissolved in 2.0 mL denatured ethanol (85%) at ambient temperature. Both materials were immediately soluble in ethanol. The reaction mixture was vigorously stirred at room temperature for 30 min. The resulting solution was a clear colorless homogenous solution. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. bath temperature resulting in a sticky liquid. The sticky liquid 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. [0165] Step 2: The dried sticky liquid (1:0:5.0 molar ratio CBD Crystal™: Tween® 80 water-soluble complex) was then dissolved in 2.0 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. The reaction appeared to form a pale-like material. The material was slowly soluble and dissolved completely producing a clear colorless homogenous as observed visually. A frothing foam formed due to the detergent nature of Tween® 80. The aqueous solution was dried over a rotary evaporator using a high vacuum at 35 °C. bath temperature to get the sticky liquid. The sticky liquid was dried over a high vacuum at room temperature for an additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0166] The resulting sticky liquid was dissolved in 2.0 mL heavy water forming a clear homogenous solution, and was analyzed by NMR. [0167] The NMR analysis confirmed that the CBD Crystal™ and Tween® 80 complex that was formed using the 1:0:5.0 molar ratio is water-soluble; the process produced a CBD Crystal™: Tween® 80 water-soluble complex without the addition of an acid when re- solubilizing the water-soluble complex in water. These data indicate that CBD is about 100% soluble in water in the presence of Tween® 80 given the height of the “A” peaks. EXAMPLE 7 – CBD Crystal™ and Tween®-80 (molar ratio of 1:2 CBD Crystal™ to
Tween® 80) [0168] The following example further indicates that Tween® 80 (Sigma-Aldrich) significantly improves the water solubility of the CBD Crystal™. [0169] Step 1: In an oven-dried single-neck RB flask equipped with a magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD Crystal™ (0.0318 mmol) and 83.3 mg Tween® 80 (0.636 mmol) (molar ratio of 1:2 CBD to Tween® 80) were weighed into the RB flask and dissolved in 2.0 mL denatured ethanol (85%) at ambient temperature. Both materials were immediately soluble in the denatured ethanol. The reaction mixture was vigorously stirred at room temperature for 30 min. The resulting solution was a clear colorless homogenous solution. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. bath temperature resulting in a sticky liquid. The sticky liquid 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. [0170] Step 2: The dried sticky liquid (1:0:2.0 molar ratio CBD Crystal™: Tween® 80 water-soluble complex) was then dissolved in 2.0 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. A light white turbid solution with bubbles formed, which remained unchanged after 30 minutes. The bubbles again were likely due to the presence of the surfactant. The pH of the solution was adjusted to ~pH 2 by the addition of 0.1 N citric acid. There was no change in solution by visual inspection. The aqueous solution was dried over a rotary evaporator using a high vacuum at 35 °C. bath temperature to obtain the sticky liquid. The sticky liquid was dried over a high vacuum at room temperature for an additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0171] The resulting dried sticky liquid was dissolved in 2.0 mL heavy water forming a slightly white turbid solution, which then was analyzed by NMR. [0172] The NMR analysis confirmed the presence of a water-soluble complex comprising the CBD and Tween® 80 at the 1:0:2.0 molar ratio; the process produced a CBD Crystal™: Tween® 80 water-soluble complex. The percentage solubility of CBD Crystal™ could not be determined from the NMR data. These data suggest that the CBD Crystal™ is made somewhat soluble in water when complexed with Tween® 80 when resolubilized in
water with the addition of citric acid.
[0173] This example further indicates that Tween® 80 (Sigma-Aldrich) significantly improves the solubility of CBD Crystal™. [0174] Step 1: In an oven-dried single-neck RB flask equipped with magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD Crystal™ (0.0318 mmol) and 41.6 mg Tween® 80 (0.0318 mmol, Sigma Aldrich) (molar ratio of 1:1 CBD to Tween® 80) were weighed into the RB flask and dissolved in 2.0 ml denatured ethanol (85%) at ambient temperature. Both materials were immediately soluble in ethanol. The reaction mixture was vigorously stirred at room temperature for 30 min. The resulting solution was a clear colorless homogenous solution. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. bath temperature resulting in a sticky liquid. The sticky liquid 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. [0175] Step 2: The dried sticky liquid (1:0:1.0 molar ratio CBD Crystal™: Tween® 80 water-soluble complex) was then dissolved in 2.0 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. A light white turbid solution with bubbles formed, which remained unchanged after 30 minutes. The pH of the solution was adjusted to ~pH 2 by the addition of 0.1 N citric acid. There was no change in solution by visual inspection. The aqueous solution was dried over a rotary evaporator using a high vacuum at 35 °C. bath temperature to get the sticky liquid. The sticky liquid was dried over a high vacuum at room temperature for an additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0176] The resulting sticky liquid was dissolved in 2 mL of heavy water forming a light white turbid and was analyzed by NMR. The NMR analysis revealed drug peaks, confirming the water solubility of the CBD Crystal™ and Tween® 80 at the 1:0:1.0 molar ratio and including citric acid when dissolved in water. The process produced a CBD: Tween® 80 water- soluble complex. The percentage solubility of CBD Crystal™ could not be determined from
the NMR data. These data further indicate that CBD can be made more soluble using this method when complexed with Tween® 80. EXAMPLE 9 – CBD Crystal™ and Poloxamer 188 (P-188) (Molar ratio of 1:0.5, CBD to P-188) [0177] The following example tested the solubility of CBD Crystal™ in water in the presence of Poloxamer 188 (P-188) (Kolliphor® P 188; BASF; CAS# 9003-11-6) in solid flake form. [0178] Step 1: In an oven-dried single-neck RB flask equipped with a magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD (0.0318 mmol) and 133 mg P-188 (0.0159 mmol) (molar ratio of 1:0.5 CBD to P-188) were weighed into the RB flask and dissolved in 2.0 mL denatured ethanol (85%) at ambient temperature. A white turbid solution with solids present formed. Two (2.0) mL of absolute methanol (MeOH) was added, and the reaction mixture was vigorously stirred at room temperature for 30 min. The resulting solution was a clear solution with solid particles present. The solution was then warmed to ~30 °C. and the solution became clear and colorless. The solvents were removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. bath temperature resulting in a white powdery product. The white powdery product was dried using vacuum drying performed at room temperature and a high vacuum pump for about one hour to remove the solvents 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. [0179] Step 2: The dried white powdery product (1:0:0.5 molar ratio CBD Crystal™: P-188) was then dissolved in 2.0 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. The solution produced is a white turbid solution. The aqueous solution was dried over a rotary evaporator using a high vacuum at 35 °C. bath temperature to get the white powdery product. The white powdery product was dried over a high vacuum at room temperature for an additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0180] The resulting white powdery product was dissolved in 2.0 mL heavy water forming a white turbid solution, and was analyzed by NMR.
[0181] The NMR analysis revealed no drug peaks (no A peaks), indicating the CBD Crystal™ in this example did not form a water-soluble complex with the P-188 surfactant under these process conditions (see FIG.4). The “B” peak(s) represent poloxamer P-188. EXAMPLE 10 – CBD Crystal™ and Poloxamer 188 (P-188) (Molar ratio of 1:0.75, CBD to P-188) [0182] The following example indicates that P-188 can improve the solubility of CBD Crystal™ in water. [0183] Step 1: In an oven-dried single-neck RB flask equipped with magnetic stir and septa (flask cap), 10 milligrams (mg) CBD Crystal™ (0.0318 mmol) and 200 mg P-188 (0.75 mmol) (molar ratio of 1:0.75 CBD to P-188) were weighed into the RB flask and dissolved in 2.0 mL denatured ethanol (85%) at ambient temperature. A white turbid solution formed. The turbid solution was heated to ~60 °C. and the solution became a clear, colorless homogenous solution by visual inspection. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. bath temperature resulting in a white powdery product. The white powdery product 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. [0184] Step 2: The dried white powdery product (1:0:0.75 molar ratio CBD: P-188) was then dissolved in 2 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. The solution was a light white turbid solution. The turbid solution was heated to ~60 °C. and the solution became a clear, colorless homogenous solution by visual inspection. The aqueous solution was dried over a rotary evaporator using a high vacuum at 35 °C. bath temperature to get the white powdery product. The white powdery product was dried over a high vacuum at room temperature for an additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0185] The resulting white powdery product was dissolved in 2.0 mL heavy water at ~25 °C. forming a clear homogenous solution, which then was analyzed by NMR.
[0186] Small drug peaks were present in the NMR analysis (FIG. 5) suggesting that some of the Crystal™ was able to form a complex with the surfactant. The NMR data indicate that CBD Crystal™ (“A” peaks) has somewhat formed a water-soluble complex using this method enhancing the water solubility of the CBD Crystal™ when using the P-188 surfactant and this method. The poloxamer P-188 is indicated as “B” peaks in FIG. 5. Notably, while the clarity of the solution improved with the addition of heat, it did not improve the formation of the complex to create a soluble form of the drug. EXAMPLE 11 – CBD Crystal™, Stevioside, and P-188 H-006-145 (Molar ratio of 1:0.75:2.0, CBD to P-188 to Stevioside) [0187] The following example indicates that Poloxamer 188 (P-188), the non-nutritive sugar stevioside did not improve the solubility of CBD Crystal™ using a combination of ethanol and methanol as solvents. [0188] Step 1: In an oven-dried single-neck RB flask equipped with a magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD (0.0318 mmol), 51.1 mg stevioside (0.0636), and 200 mg P-188 (0.02381 mmol) (molar ratio of 1:0.75:2 CBD to P-188 to stevioside) were weighed into the RB flask and dissolved in 3.0 mL denatured ethanol (85%) at ambient temperature. When water was added, the solution became a white turbid solution with solids in it. Three (3.0) mL of methanol (MeOH) was added while vigorously stirring. The solution became a clear, colorless homogenous solution by visual inspection. Ethanol, water, and methanol were removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. bath temperature resulting in a white powdery product. The white powdery product was dried using vacuum drying performed at room temperature and a high vacuum pump for about one hour to remove the ethanol, water, and methanol 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. [0189] Step 2: The dried white powdery product (1:0:0.75:2.0 molar ratio CBD:P-188: stevioside complex) was then dissolved in 3.0 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at ambient temperature for 30 min. The solution was a clear homogenous solution, which remained unchanged after 30 minutes. The aqueous solution was dried over a high vacuum at room temperature for an
additional hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. [0190] The resulting white powdery product was dissolved in 2.0 mL heavy water forming a light white turbid solution, which was then analyzed by NMR as before. [0191] The NMR sample was light white and turbid. The NMR analysis (FIG. 6) revealed no drug peaks (A peaks), indicating that the CBD Crystal™ did not form a water- soluble complex in the presence of P-188 and stevioside when using a combination of ethanol, methanol, and water. EXAMPLE 12 – CBD Crystal™, Stevioside, and P-188 (Molar ratio of 1:0.75:3.0, CBD to P-188 to Stevioside) [0192] The following example indicates that Poloxamer 188 and stevioside, improve the solubility of CBD Crystal™ under the indicated process conditions. [0193] Step 1: In an oven-dried single-neck RB flask equipped with a magnetic stir bar and septa (flask cap), 10 milligrams (mg) CBD Crystal™ (0.0318 mmol), 77 mg stevioside (0.0954), and 200 mg P-188 (0.002381 mmol) (molar ratio of 1:0.75:3 CBD to P-188 to stevioside) were weighed into the RB flask and dissolved in 3.0 mL denatured ethanol (85%) at ambient temperature. The solution was white and turbid with solids in it at room temperature. The solution was heated to ~60 °C. to see if the addition of heat improved the solubility of the components and then the formation of the complex. P-188 has a melting point of about 52 °C. During the heating step, it was observed that the solution became clear and colorless at ~40 °C. After heating, the solution was cooled to room temperature; the solution remained a clear colorless homogenous solution. Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at 35 °C. bath temperature resulting in a white powdery product. The powdery product was dried using vacuum drying performed at room temperature and a high vacuum pump for about one hour to remove the ethanol, 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. [0194] Step 2: The dried white powdery product (1:0:0.75:3.0 molar ratio CBD:P-188: stevioside complex) was then dissolved in 2.0 mL deionized water (DI) at room temperature in an RB flask with a magnetic stir bar. The reaction mixture was stirred at room temperature for 30 min. The solution was clear and homogenous and remained unchanged after 30 minutes.
The aqueous solution was dried over a high vacuum at room temperature for an hour to remove the water completely. The weight of the material was checked while drying; the material was dried until no further weight loss was detected. The yield was quantitative. [0195] The resulting dried crystalline product was dissolved in 2.0 mL heavy water forming a clear homogenous solution, which was then analyzed by NMR. [0196] Drug peaks were present in the NMR analysis (FIG. 7A), although the ratio could not be readily determined from the NMR data. These data indicate that CBD Crystal™ using this method forms a water-soluble complex. Based on the height of peak A, the CBD Crystal™ had improved solubility over the lower temperature compared to the CBD Crystal™ not complexed with the surfactant. [0197] The NMR analysis was repeated, but this time the NMR tube was heated to ~30 °C. and then NMR (FIG.7B). The drug peak obtained when using the higher temperature for the NMR analysis indicates a greater signal for the ”A” peaks than obtained without heating the cuvette to 30 °C as reflected in FIG.7A. EXAMPLE 13 – Dispersion rates for a CBD Crystal™:Stevioside:Tween®80 Complex [0198] A complex was formed with a 1:2:1 ratio of CBD Crystal™:Stevioside:Tween®80. The water-soluble complex of this 1:2:1 ratio was made using the methods as described for Example 8, but at a different ratio and using also the non- nutritive sugar, stevioside. The sample was analyzed at 25 ºC for 80 sec and at a count rate of 145.7 kcps (145,000 counts per second) at measurement position 4.65. This experiment revealed a peak having 99.0% intensity. EMBODIMENTS [0199] The following embodiments are examples of the water-soluble complexes, methods of making said complexes, compositions comprising such complexes, and methods for using the complexes. [0200] Embodiment 1. A water-soluble complex comprising a sugar and a poorly water-soluble drug (PSD) or drug compound, which complex comprises: a molar ratio of up to about 5 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-β-D-maltoside, stevioside, or rebaudioside A, provided that said water-soluble complex has at least a five (5) fold increase in the water solubility of said poorly soluble drug or drug compound at 20º C. as compared
to the water solubility of said drug not in said water-soluble complex; and further provided that a maximum amount of the sugar in a daily unit dose of said complex is no more than about 10 mg/kg, and wherein the PSD or drug compound is a cannabinoid/endocannabinoid. [0201] Embodiment 2. The water-soluble complex of Embodiment 1, wherein the PSD or drug compound is a cannabicyclol, a cannabichromene, a cannabielsoin, a cannabitriol, a cannabidiol, a cannabigerol, a cannabinol, a cannabinodiol, a delta-tetrahydrocannabinol, a delta-tetrahydrocannabinol, or a pharmaceutically acceptable salt of any thereof. [0202] Embodiment 3. The water-soluble complex of Embodiment 1, wherein the PSD or drug compound is delta-8-tetrahydrocannabinol (Δ8-THC), delta-8-tetrahydrocannabinolic acid (Δ8-THCA), delta-9-tetrahydrocannabinol (Δ9-THC or THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), and tetrahydrocannabinolic acid (THCA), or cannabiidiolic acid (CBDA). [0203] Embodiment 4. The water-soluble complex of any of Embodiments 1-3, wherein the sugar is rubusoside, rebaudioside A, dodecyl-β-D-maltoside, dulcoside B, or stevioside. [0204] Embodiment 5. The water-soluble complex of Embodiment 4, wherein the sugar is rubusoside or stevioside. [0205] Embodiment 6. The water-soluble complex of any of Embodiments 1-5, wherein the amount of the sugar in the daily unit dose is no more than 5 mg/kg. [0206] Embodiment 7. The water-soluble complex of any of Embodiments 1-5, wherein the amount of the sugar in the daily unit dose is no more than about 280 mg. [0207] Embodiment 8. The water-soluble complex of any of Embodiments 1-5, wherein said water-soluble complex comprises a molar ratio of about 1:1 to about 1:12 moles of the PSD or drug compound to mole of sugar. [0208] Embodiment 9. The water-soluble complex of any of Embodiments 1-5, wherein said water-soluble complex comprises a molar ratio of about 2 to about 10 moles of the sugar for each mole of said PSD or drug compound. [0209] Embodiment 10. The water-soluble complex of Embodiment 9, wherein said water-soluble complex comprises a molar ratio of about 3 moles of the sugar for each mole of said PSD or drug compound. [0210] Embodiment 11. The water-soluble complex of any of Embodiments 1-5, wherein said PSD or drug compound is stable in water at pH 8.5 for at least 2 hours. [0211] Embodiment 12. The water-soluble complex of any of Embodiments 1-5,
wherein said water-soluble complex is stable in water at pH 4 for at least 2 hours. [0212] Embodiment 13. A dried form of the water-soluble complex of any of Embodiments 1-13, wherein the dried form is stable at 30 °C for at least 90 days. [0213] Embodiment 14. The water-soluble complex of any of Embodiments 1 to 13, wherein the water-soluble complex is in the form of a powder, a tablet, an orally disintegrating tablet, a capsule, a liquid, a gel, a thin film, a lozenge, an effervescent powder or tablet, an emulsion, or formulated for parenteral administration. [0214] Embodiment 15. The water-soluble complex of Embodiment 14, wherein the formulation for parenteral administration is to be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intrathecal, or intravenously. [0215] Embodiment 16. The water-soluble complex of any of Embodiments 1 to 13, 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. [0216] Embodiment 17. A water-soluble complex comprising a sugar and a poorly water-soluble drug (PSD) or drug compound, which water-soluble complex comprises: a molar ratio of about 3 moles of the sugar for each mole of said PSD or drug compound, wherein the sugar is one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; 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 a five (5) fold increase in the water solubility of said PSD or drug compound, at 20º C as compared to the water solubility of said PSD or drug compound that is not in the water-soluble complex; and further provided that a maximum amount of the sugar in a daily unit dose of said water-soluble complex is no more than about 280 mg. [0217] Embodiment 18. A method of making a water-soluble complex comprising a sugar and a poorly water-soluble drug (PSD) or drug compound, the method comprising the steps of admixing, in at least 85% ethanol, the sugar with the PSD or drug compound in a molar ratio of from about 2 to about 5 moles of the sugar for each mole of said PSD or drug compound until solubilized thereby forming the water-soluble complex, wherein formation of the water-soluble complex can be determined by nuclear magnetic resonance spectroscopy, and wherein the sugar is one or more of rubusoside,
rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; and wherein the admixing step is optionally performed with a pharmaceutically acceptable acid; and optionally drying the water-soluble complex. [0218] Embodiment 19. The method of Embodiment 18, wherein the sugar is rubusoside or stevioside. [0219] Embodiment 20. The water-soluble complex of any of Embodiments 18 or 19, wherein the PSD or drug compound is a cannabicyclol, a cannabichromene, a cannabielsoin, a cannabitriol, a cannabidiol, a cannabigerol, a cannabinol, a cannabinodiol, a delta- tetrahydrocannabinol, a delta-tetrahydrocannabinol, or a pharmaceutically acceptable salt of any thereof. [0220] Embodiment 21. The method of Embodiment 18, wherein the method further comprises drying the water-soluble complex. [0221] Embodiment 22. The method of Embodiment 21, wherein the dried water- soluble complex is resolubilized in a liquid. [0222] Embodiment 23. The method of Embodiment 18, wherein the admixing step is in the presence of a sufficient amount of a pharmaceutically acceptable acid to solubilize and render the reaction mixture homogeneous and clear. [0223] Embodiment 24. The method of Embodiment 23, 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. [0224] Embodiment 25. The method of Embodiment 18, wherein said formed water- soluble complex comprises a molar ratio of about 2 to about 5 moles of the sugar for each mole of said PSD or drug compound. [0225] Embodiment 26. The method of Embodiment 25, wherein the sugar is rubusoside or stevioside. [0226] Embodiment 27. The method of Embodiment 26, wherein said formed water- soluble complex comprises a molar ratio of about 2 to about 4.5 moles of the sugar for each mole of said PSD or drug compound. [0227] Embodiment 28. The method of Embodiment 27, wherein the sugar is rubusoside or stevioside. [0228] Embodiment 29. The method of Embodiment 25, wherein said formed water-
soluble complex comprises a molar ratio of about 3 moles of the sugar for each mole of said PSD or drug compound. [0229] Embodiment 30. The method of Embodiment 29, wherein the sugar is rubusoside or stevioside. [0230] Embodiment 31. The method of Embodiment 18, wherein said formed water- soluble complex is stable in water at pH 8.5 for at least 2 hours. [0231] Embodiment 32. The method of Embodiment 18, wherein said formed water- soluble complex is stable in water at pH 4 for at least 2 hours. [0232] Embodiment 33. The method of Embodiment 21, wherein said method further comprises drying the water-soluble complex by freeze-drying or lyophilizing. [0233] Embodiment 34. The method of Embodiment 33, wherein the dried water- soluble complex is formulated into a pill or a pharmaceutically acceptable liquid. [0234] These further embodiments are contemplated. [0235] Embodiment 1A. A water-soluble complex comprising a sugar, a polysorbate or poloxamer surfactant, and a poorly water-soluble drug (PSD) or drug compound, which complex comprises: a molar ratio of up to about 12.0 moles of the sugar and 12.0 moles of the polysorbate or poloxamer surfactant for each mole of said PSD or drug compound, wherein the sugar is one or more of rubusoside, dulcoside B, dodecyl-β-D- maltoside, stevioside, or rebaudioside A, and wherein the polysorbate surfactant is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, and Polysorbate 80, or wherein the poloxamer surfactant is Poloxamer 188 (P188), provided that said water-soluble complex has at least a five (5) fold increase in the water solubility of said poorly soluble drug or drug compound at 20º C as compared to the water solubility of said PSD or drug compound not in said water-soluble complex; and further provided that the sugar in a daily unit dose of said complex is no more than about 10.0 mg/kg, and wherein the PSD or drug compound is a cannabinoid/endocannabinoid. [0236] Embodiment 2A. The water-soluble complex of Embodiment 1A, wherein the PSD or drug compound is a cannabicyclol, a cannabichromene, a cannabielsoin, a cannabitriol, a cannabidiol, a cannabigerol, a cannabinol, a cannabinodiol, a delta- tetrahydrocannabinol, or a pharmaceutically acceptable salt of any thereof. [0237] Embodiment 3A. The water-soluble complex of Embodiment 1A, wherein the PSD or drug compound is delta-8-tetrahydrocannabinol (Δ8-THC), delta-8- tetrahydrocannabinolic acid (Δ8-THCA), delta-9-tetrahydrocannabinol (Δ9-THC or THC), Δ8-THC acetate ester, Δ9-THC acetate ester, cannabidiol (CBD), cannabinol (CBN),
cannabigerol (CBG), cannabichromene (CBC), and tetrahydrocannabinolic acid (THCA), or cannabidiolic acid (CBDA). [0238] Embodiment 4A. The water-soluble complex of any of Embodiments 1- 3A, wherein the sugar is rubusoside, rebaudioside A, dodecyl-β-D-maltoside, dulcoside B, or stevioside. [0239] Embodiment 5A. The water-soluble complex of Embodiment 4A, wherein the sugar is rubusoside or stevioside. [0240] Embodiment 6A. The water-soluble complex of any of Embodiments 1- 5A, wherein the amount of the sugar in the daily unit dose is no more than about 5.0 mg/kg. [0241] Embodiment 7A. The water-soluble complex of any of Embodiments 1- 5A, wherein the amount of the sugar in the daily unit dose is no more than about 280.0 mg. [0242] Embodiment 8A. The water-soluble complex of any of Embodiments 1- 7A, wherein the polysorbate surfactant is Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80. [0243] Embodiment 9A. The water-soluble complex of any of Embodiments 1- 8A, wherein said water-soluble complex comprises a molar ratio of the PSD or drug compound to mole of sugar to mole of polysorbate surfactant (Drug:sugar:PSS) of about 1:1:1 to about 1:10:10 moles. [0244] Embodiment 10A. The water-soluble complex of any of Embodiments 1- 8A, wherein said water-soluble complex comprises a molar ratio of about 2.0 to about 10.0 moles of the sugar and about 2.0 to about 10.0 moles of the PSS, for each mole of said PSD or drug compound (from about 1:2:2 to about 1:10:10 molar ratio of Drug:sugar:PSS). [0245] Embodiment 11A. The water-soluble complex of Embodiment 9A, wherein said water-soluble complex comprises a molar ratio of about 3.0 moles of the sugar and about 5.0 moles of the PSS for each mole of said PSD or drug compound (about 1:3:5 molar ratio of Drug sugar:PSS). [0246] Embodiment 12A. The water-soluble complex of any of Embodiments 1- 7A, wherein the poloxamer surfactant is Poloxamer 188. [0247] Embodiment 13A. The water-soluble complex of any of Embodiments 1-7A and 12A, wherein said water-soluble complex comprises a molar ratio of the PSD or drug compound to mole of sugar to mole of polysorbate surfactant (Drug:sugar:PXS) of about 1:1.0:0.5 to about 1:12.0:5.0 moles. [0248] Embodiment 14A. The water-soluble complex of any of Embodiments 1- 7A, 12A, and 13A, wherein said water-soluble complex comprises a molar ratio of about 4.0
to about 12.0 moles of the sugar and about 0.50 to about 3.0 moles of the PXS, for each mole of said PSD or drug compound (from about 1:4.0:0.5 to about 1:12.0:3.0 molar ratio of PSD:sugar:PXS). [0249] Embodiment 15A. The water-soluble complex of Embodiment 13A, wherein said water-soluble complex comprises a molar ratio of about 12.0 moles of the sugar and about 3.0 moles of the PXS for each mole of said PSD or drug compound (about 1:12.0:3.0 molar ratio of PSD:sugar:PXS). [0250] Embodiment 16A. The water-soluble complex of any of Embodiments 1- 15A, wherein said PSD or drug compound is stable in water at pH 8.5 for at least 2 hours. [0251] Embodiment 17A. The water-soluble complex of any of Embodiments 1- 16A, wherein said water-soluble complex is stable in water at about pH 4.0 for at least 2 hours. [0252] Embodiment 18A. A dried form of the water-soluble complex of any of Embodiments 1-17 which is stable at 30°C for at least 90 days. [0253] Embodiment 19A. The water-soluble complex of any of Embodiments 1A to 18A, wherein the water-soluble complex is in the form of a powder, a tablet, an orally disintegrating tablet, a capsule, a liquid, a gel, a thin film, a lozenge, an effervescent powder or tablet, an emulsion, or formulated for parenteral administration. [0254] Embodiment 20A. The water-soluble complex of Embodiment 16A, wherein the formulation for parenteral administration is to be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, intrathecal, or intravenously. [0255] Embodiment 21A. The water-soluble complex of any of Embodiments 1A to 18A, 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. [0256] Embodiment 22A. A water-soluble complex comprising a sugar, a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), and a poorly water-soluble drug (PSD) or drug compound, which water-soluble complex comprises: a molar ratio of about 1 to 12 moles of the sugar and about 0.5 to 12.0 moles of the PSS or PXS, for each mole of said PSD or drug compound, wherein the sugar is one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside, and wherein the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, and Polysorbate 80, and wherein the poloxamer surfactant is Poloxamer 188; wherein said water-soluble complex is stable in water at about pH 8.5 and at about pH 4.0 for at least 2 hours each; provided that said water-soluble complex has at least a five (5) fold increase in the water solubility of said PSD
or drug compound, at 20 ºC. as compared to the water solubility of said PSD or drug compound that is not in the water-soluble complex; and further provided that a maximum amount of the sugar in a daily unit dose of said water-soluble complex is no more than about 280.0 mg, wherein said PSD or drug compound is a cannabinoid/endocannabinoid. [0257] Embodiment 23A. A method of making a water-soluble complex comprising a sugar, a polysorbate surfactant (PSS) or a poloxamer surfactant (PXS), and a poorly water-soluble drug (PSD) or drug compound, the method comprising the steps of: admixing, in at least 85% ethanol, the sugar and the PSS or PXS with the PSD or drug compound in a molar ratio of from about 1 to about 12 moles of the sugar and about 0.5 to about 12.0 moles of the PSS or PXS for each mole of said PSD or drug compound until solubilized thereby forming the water-soluble complex, wherein the formation of the water- soluble complex can be determined by nuclear magnetic resonance spectroscopy, and wherein the sugar is one or more of rubusoside, rebaudioside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; and the PSS is one or more of Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, and Polysorbate 80 and wherein the poloxamer surfactant is Poloxamer 188, wherein the admixing step is optionally performed with a pharmaceutically acceptable acid; and optionally drying the water-soluble complex. [0258] Embodiment 24A. The method of Embodiment 23A, wherein the sugar is stevioside, and the PSS is Polysorbate 20 or Polysorbate 80. [0259] Embodiment 25A. The method of Embodiment 23A, wherein the sugar is stevioside, and the PXS is Poloxamer 188. [0260] Embodiment 26A. The method of Embodiment 25A, wherein the admixing step further comprises heating the reaction mixture, for instance up to about 60°C., to melt the PXS and facilitate solubilizing the drug in the reaction mixture. [0261] Embodiment 27A. The method of any one of Embodiments 23-26A, wherein the PSD is a cannabicyclol, a cannabichromene, a cannabielsoin, a cannabitriol, a cannabidiol, a cannabigerol, a cannabinol, a cannabinodiol, a delta-tetrahydrocannabinol, or a pharmaceutically acceptable salt of any thereof. [0262] Embodiment 28A. The method of Embodiment 23A, wherein the method further comprises drying the water-soluble complex. [0263] Embodiment 29A. The method of Embodiment 28A, wherein the dried water-soluble complex is resolubilized in a liquid. [0264] Embodiment 30A. The method of Embodiment 23A, wherein the admixing step is in the presence of a sufficient amount of a pharmaceutically acceptable acid to solubilize
and render the reaction mixture homogeneous and clear. [0265] Embodiment 31A. The method of Embodiment 30A, 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. [0266] Embodiment 32A. The method of Embodiment 23A, wherein said formed water-soluble complex comprises a molar ratio of about 2.0 to about 5.0 moles of the sugar and about 2.0 to about 5.0 moles of the PSS for each mole of said PSD or drug compound. [0267] Embodiment 33A. The method of Embodiment 32A, wherein the sugar is stevioside, and the PSS is Polysorbate 20 or Polysorbate 80. [0268] Embodiment 34A. The method of Embodiment 32A, wherein said formed water-soluble complex comprises a molar ratio of about 4.0 to about 12.0 moles of the sugar and about 0.5 to about 3.0 moles of the PXS for each mole of said PSD or drug compound. [0269] Embodiment 35A. The method of Embodiment 34A, wherein the sugar is stevioside, and the PXS is Poloxamer 188. [0270] Embodiment 36A. The method of Embodiment 23A, wherein said formed water-soluble complex comprises a molar ratio of about 2.0 to about 4.5 moles of the sugar for each mole of said PSD or drug compound. [0271] Embodiment 37A. The method of Embodiment 36A, wherein the sugar is stevioside, and the PSS is Polysorbate 20 or Polysorbate 80. [0272] Embodiment 38A. The method of Embodiment 23A, wherein said formed water-soluble complex comprises a molar ratio of about 12.0 moles of the sugar for each mole of said PSD or drug compound. [0273] Embodiment 39A. The method of Embodiment 38A, wherein the sugar is stevioside, and the PXS is Poloxamer 188. [0274] Embodiment 40A. The method of Embodiment 23A, wherein said formed water-soluble complex comprises a molar ratio of about 12.0 moles of the sugar and about 0.75 moles of the PXS for each mole of said PSD or drug compound. [0275] Embodiment 41A. The method of Embodiment 40A, wherein the sugar is stevioside, and the PXS is Poloxamer 188. [0276] Embodiment 42A. The method of Embodiment 23A, wherein said formed water-soluble complex comprises a molar ratio of about 12.0 moles of the sugar and about 0.75 moles of the PXS for each mole of said PSD or drug compound.
[0277] Embodiment 43A. The method of Embodiment 42A, wherein the sugar is stevioside, and the PXS is Poloxamer 188. [0278] Embodiment 44A. The method of Embodiment 23A, wherein said formed water-soluble complex is stable in water at about pH 5 to about 8.5 for at least 2 hours. [0279] Embodiment 45A. The method of Embodiment 23A, wherein said formed water-soluble complex is stable in water at about pH 4.0 to about 5.5 for at least 2 hours. [0280] Embodiment 46A. The method of Embodiment 23A, wherein said method further comprises drying the water-soluble complex comprising PSS by freeze-drying or lyophilizing or comprises drying the water-soluble complex comprising PXS by freeze-drying. [0281] Embodiment 47A. The method of Embodiment 46A, wherein the dried water-soluble complex is formulated into a pill or a pharmaceutically acceptable liquid. [0282] Embodiment 1B. A water-soluble complex comprising a surfactant and a drug compound, which water-soluble complex comprises: i) the surfactant in about 0.5 to 12.0 moles of the surfactant to each mole of the drug compound, ii) the drug compound is one or more of a cannabinoid or an endocannabinoid or its salt, solvate, co-crystal, or polymorph; and iii) optionally a non-nutritive sugar, wherein if the non-nutritive sugar is present it is in a molar ratio of about 1 to 20 moles of the non-nutritive sugar to the drug compound, and the non- nutritive sugar is one or more of ADVANTAME®, NEOTAME®, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-β-D-maltoside (DDM), stevioside, or rebaudioside A; 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. [0283] Embodiment 2B. A water-soluble complex comprising a surfactant and a
drug compound of formula (VII) below: [
^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^] ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ (VII) wherein p can be an integer from 1 to 5; the drug compound (“Drug”) is one or more of a cannabinoid or endocannabinoid; the water-soluble complex is formed by admixing the surfactant the drug compound in a solvent until solubilized optionally with a pharmaceutically acceptable acid, drying the solvent from the drug compound and the surfactant, dissolving the dried drug compound and surfactant in water forming the water-soluble complex optionally in a pharmaceutically acceptable acid, and the drug compound has an increased water solubility at 20 ºC in the form of the water-soluble complex than the drug compound not in the water- soluble complex. [0284] Embodiment 3B. The water-soluble complex of Embodiment 1B or
Embodiment 2B, wherein the water-soluble complex has at least a two-fold increase in the water solubility of the drug compound in the water-soluble complex at 20º C as compared to the water solubility of the drug compound not in the water-soluble complex. [0285] Embodiment 4B. The water-soluble complex of Embodiments 1B to 3B, wherein the surfactant is a non-ionic surfactant. [0286] Embodiment 5B. The water-soluble complex of Embodiment 1, wherein the non-ionic surfactant is a polysorbate or a poloxamer. [0287] Embodiment 6B. The water-soluble complex of Embodiment 5B, wherein the drug compound to surfactant is in a molar ratio from about 1:0.5 to about 1:3.0. [0288] Embodiment 7B. The water-soluble complex of Embodiment 6B, wherein the drug compound to surfactant is in a molar ratio of about 1:3.0. [0289] Embodiment 8B. The water-soluble complex of any of Embodiments 4- 7B, wherein the poloxamer surfactant is Poloxamer 188. [0290] Embodiment 9B. The water-soluble complex of Embodiment 5B, wherein the surfactant is a polysorbate, and the drug compound to polysorbate surfactant is in a molar ratio from about 1:1 to about 1:10. [0291] Embodiment 10B. The water-soluble complex of Embodiment 9B, wherein the drug compound to polysorbate surfactant is in a molar ratio from about 1:2 to about 1:10. [0292] Embodiment 11B. The water-soluble complex of any of claims 9B to 10B, wherein the polysorbate surfactant is Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, or Polysorbate 80. [0293] Embodiment 12B. The water-soluble complex of Embodiment 1B, wherein the non-nutritive sugar is present and is rubusoside, dulcoside B, dodecyl-β-D-maltoside (DDM), stevioside, or rebaudioside A. [0294] Embodiment 13B. The water-soluble complex of Embodiment 12B, wherein the non-nutritive sugar is rubusoside or stevioside. [0295] Embodiment 14B. The water-soluble complex of any of Embodiments 1B to 13B, wherein the water-soluble complex has at least a 50% increase in the water solubility of the drug compound in the form of the water-soluble complex at 20º C. as compared to the water solubility of the drug compound not in the water-soluble complex. [0296] Embodiment 15B. The water-soluble complex of any of Embodiments 1B to 14B, wherein the cannabinoid is delta-8-tetrahydrocannabinol (Δ8-THC), delta-8- tetrahydrocannabinolic acid (Δ8-THCA), delta-9-tetrahydrocannabinol (Δ9-THC or THC), delta-9-tetrahydrocannabivarin (THCV), Δ8-THC acetate ester, Δ9-THC acetate ester,
cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), 11-hydroxyl- Δ9-THC, cannabichromene, cannabidivarin (CBDV), dronabinol, nabilone, nabiximols, and tetrahydrocannabivarin; and the endocannabinoid is 2- arachidonoylglycerol (2-AG), anandamide (ANA), N-acylethanolamine (NAE), or N-linoleoyl ethanolamine (LLEA), or a pharmaceutically acceptable salt, solvate, co-crystal or polymorph of any of thereof, or a combination of any cannabinoid. [0297] Embodiment 16B. The water-soluble complex of any of Embodiments 1B to 14B, wherein the cannabinoid is a synthetic or naturally extracted cannabinoid selected from a delta-8-tetrahydrocannabinol (Δ8-THC), delta-9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), delta-9-tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), or a pharmaceutically acceptable salt, a solvate, co-crystal or polymorph of any of thereof or a combination of any cannabinoid. [0298] Embodiment 17B. The water-soluble complex of any of Embodiments 12B to 13B, wherein the non-nutritive sugar is present in a daily unit dose amount of no more than about 280.0 mg or at no more than 10 mg/kg weight of a subject. [0299] Embodiment 18B. The water-soluble complex of Embodiment 2B, 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. [0300] Embodiment 19B. A dried form of the water-soluble complex of any of Embodiments 1B to 18B, which is stable at 30°C for at least 90 days. [0301] Embodiment 20B. A composition comprising the water-soluble complex of any of Embodiments 1B to 19B and a pharmaceutically acceptable stabilizer, excipient, and/or carrier. [0302] Embodiment 21B. The composition of Embodiment 20B, wherein the water-soluble complex is formulated as a powder, a tablet, an orally disintegrating tablet, a capsule, a gummy, a liquid, an elixir, an emulsion, a chewing gum, a lollipop, a sublingual drop, a soft gel, a tincture, a syrup, a gel, a thin film, a lozenge, an effervescent powder or tablet, an emulsion, or for parenteral administration.
[0303] Embodiment 22B. The composition of Embodiment 20B, wherein the water-soluble complex is for intradermal, subcutaneous, intramuscular, intraperitoneal, intrathecal, or intravenous administration. [0304] Embodiment 23B. A method of making a water-soluble complex comprising a surfactant and a drug compound, the method comprising the steps of: a) admixing, in one or more solvents, the surfactant and the drug compound, and optionally a non-nutritive sugar until solubilized thereby forming the water-soluble complex optionally in the presence of a pharmaceutically acceptable acid, wherein the drug compound to the surfactant is in a molar ratio from about 0.5 to about 12.0 and the drug compound to the non-nutritive sugar is in a molar ratio from about 1.0 to about 20.0; b) drying the solvent from the drug compound, surfactant, and the optional pharmaceutically acceptable acid and the non-nutritive sugar; c) dissolving the water-soluble complex of step a) in water, wherein dissolving optionally is in the presence of a pharmaceutically acceptable acid; and the drug compound in the water- soluble complex is determinable by nuclear magnetic resonance spectroscopy (NMR); and wherein the non-nutritive sugar is one or more of ADVANTAME®, NEOTAME®, thaumatin, saccharin, sucralose, Lou Han Guo, aspartame, acesulfame potassium, allulose, rubusoside, dulcoside B, dodecyl-β-D-maltoside, stevioside, or rebaudioside A, and the drug compound is one or more of an endocannabinoid or a cannabinoid. [0305] Embodiment 24B. The method of Embodiment 23B, wherein the solvent is one or more solvents selected from: acetonitrile, chloroform, chlorobenzene, cyclohexane, cumene, 1,2-dichloroethene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, ethanol, formamide, hexane, methanol, 2-methoxyethanol, methylbutylketone, methylcyclohexane, methylisobutylketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetralin, toluene, 1,1,2-trichloroethene, or xylene. [0306] Embodiment 25B. The method of Embodiment 23B, wherein the one or more solvents are selected from chloroform, ethanol, methanol, or a combination thereof. [0307] Embodiment 26B. The method of any of Embodiments 23B to 25B, 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. [0308] Embodiment 27B. The method of any of Embodiments 23B to 25B, wherein
the optional non-nutritive sugar is present and is rubusoside, dulcoside B, dodecyl-β-D- maltoside (DDM), stevioside, or rebaudioside A. [0309] Embodiment 28B. The method of Embodiment 27B, wherein the optional non-nutritive sugar is rubusoside or stevioside. [0310] Embodiment 29B. The method of any of Embodiments 23B to 28B, wherein the admixing step further comprises heating the solvent, the surfactant, the drug compound, and if present the optional non-nutritive sugar the optional pharmaceutically acceptable acid to about 60 °C. [0311] Embodiment 30B. The method of any of Embodiments 23B to 28B, wherein the water-soluble complex has at least a two-fold increase in the water solubility of the drug compound in the water-soluble complex at 20º C as compared to the water solubility of the drug compound not in the water-soluble complex [0312] Embodiment 30. A method of treating a subject having a condition with the water-soluble complex of any one of Embodiments 1B to 18B or the composition of any of Embodiments 20B to 22B, wherein the subject has a disease or a condition arising from the condition is selected from anxiety, cachexia, post-traumatic stress disorder (PTSD), spasticity, Alzheimer’s Disease (AD), dystonia, schizophrenia, agitation arising from AD, pain, a seizure disorder, pain, inflammation, fibromyalgia, Huntington’s disease (HD), multiple sclerosis (MS), inflammatory bowel syndrome (IBS), appetite stimulation, cachexia, and chemotherapy- induced nausea, or vomiting (CINV). [0313] Embodiment 31B. The water-soluble complex of any of Embodiments 1B to 18B or the composition of any of Embodiments 20B to 22B for use as a medicament in the treatment of a disease or a condition arising from the disease or condition selected from anxiety, cachexia, post-traumatic stress disorder (PTSD), spasticity, Alzheimer’s Disease (AD), dystonia, schizophrenia, agitation arising from AD, pain, a seizure disorder, pain, inflammation, fibromyalgia, Huntington’s disease (HD), multiple sclerosis (MS), inflammatory bowel syndrome (IBS), appetite stimulation, cachexia, or chemotherapy-induced nausea and vomiting (CINV). [0314] Embodiment 32B. The use of the water-soluble complex of any of Embodiments 1B to 18B or the composition of any of Embodiments 20B to 22B for the manufacture of a medicament for the treatment of a disease or a condition arising from the disease or condition selected from anxiety, cachexia, post-traumatic stress disorder (PTSD), spasticity, Alzheimer’s Disease (AD), dystonia, schizophrenia, agitation arising from AD, pain, a seizure disorder, pain, inflammation, fibromyalgia, Huntington’s disease (HD), multiple
sclerosis (MS), inflammatory bowel syndrome (IBS), appetite stimulation, cachexia, and chemotherapy-induced nausea, or vomiting (CINV).
is the ratio of PSS to drug compound. The PSS-containing water-soluble complex remains 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). [0096] A “water-soluble complex comprising a poloxamer surfactant is reflected in formula (IV): [ ^^^^ ^^^^ ^^^^ ^^^^ ^^^^ ] ^^^^ [ ^^^^ ^^^^ ^^^^ ] ^^^^[ ^^^^ ^^^^ ^^^^ ^^^^]) 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 drug compound for the purposes described herein (e.g., therapeutic administration to a subject). “p” is the ratio of non-nutritive sugar to drug compound and