TW202435892A - Compositions and methods for improving the solubility of erectile dysfunction therapeutics - Google Patents

Abstract

A method is disclosed for improving the solubility of a poorly soluble drug compound such as by mixing the poorly water-soluble drug compound (such as alprostadil, sildenafil, tadalafil, vardenafil, avanafil, or a pharmaceutically acceptable salt of any thereof) with a non-nutritive sugar such as rubusoside, rebaudioside A, dulcoside B, dodecyl-[beta]-D-maltoside (DDM), or stevioside, or any combination thereof in the presence of a pharmaceutically acceptable solvent such as ethanol and then removing the solvent to creating a water-soluble drug-sugar complex.

Description

Compositions and methods for improving the solubility of erectile dysfunction therapeutics

Disclosed are water-soluble compound-sugar complexes comprising: a non-nutritional sugar, such as diterpene diglycoside ("DTG"), triterpene glycoside or other listed sugars; and a poorly soluble drug, its salt or a free form of the drug or a pharmaceutically acceptable salt thereof, wherein the water-soluble complex formed by the sugar and the compound significantly enhances the solubility of the poorly soluble drug for administration to an individual. Also disclosed are methods for preparing the complexes and pharmaceutical compositions comprising the complexes.

The solubility of many compounds can play a critical role in their commercial utility, especially in the pharmaceutical industry. The water solubility of a drug plays an important role in the effectiveness of a compound as a drug, especially in many basic pharmacokinetic (PK) properties. Poor water solubility of a drug can directly lead to insufficient absorption, poor C _max properties (e.g., maximum blood concentration), and similar disadvantages. If the water solubility of a drug is insufficient, it may not be fully absorbed into the individual's blood circulation, resulting in insufficient C _max and ineffectiveness (e.g., Ganesan et al., "Solubility: a speed-breaker on the drug discovery highway", Bioequiv . Availab . 3(3): 56-8, 2017, Editorial).

It is well known that many commercial erectile dysfunction (ED) drugs generally have poor water solubility. At physiological pH and 37°C, water-soluble drugs dissolve in amounts greater than 10 mg/mL. A poorly water-soluble drug is any drug that dissolves at physiological pH and at 37°C in amounts less than 1 mg/mL. Sildenafil citrate (SLC), sold under the brand names Viagra ^® and Revatio ^® , is considered to have low water solubility, resulting in delayed onset of action and/or poor bioavailability when administered to a subject (i.e., it has a water solubility of 4.1 ± 1.3 mg/ml in distilled water). Tadalafil (Cialis®) is considered to be virtually insoluble in water, resulting in highly volatile blood levels and irreproducible clinical effects. Vardenafil HCl (brand name Levitra® or Staxyn®) has a water solubility of 0.11 mg/mL, which results in variable drug response in a given subject to which vardenafil is administered. Avanafil (brand name Stendra®) has a water solubility of less than 1.0 mg/mL at 25°C and less than 1 mg/mL in ethanol at 25°C.

In various cases, the poor water solubility of erectile dysfunction ("PWS-ED") drugs can negatively impact the use of these drugs due to lack of reproducible results and/or slow onset of activity.

Additionally, alprostadil, another ED drug, is also used to temporarily patency arterial catheters in newborns with congenital heart disease prior to surgical intervention. It and sildenafil are both phosphodiesterase-5 inhibitors. It is administered in the form of an injection as well as a suppository. Additionally, it is formulated as a topical cream (Vitaros® Cream) with skin penetration that enhances drug delivery.

Developing methods to render poorly soluble drugs substantially more soluble in aqueous environments could rescue drugs that have shown promise in treating disease but are not commercially viable due to insufficient solubility.

There has long been a search for new means of making existing poorly water soluble ("PWS") erectile dysfunction ("ED") drugs, PWS-ED drugs, more soluble, both for FDA-approved ED drugs and for other drugs. Water-soluble complexes of a non-nutritional sugar, such as a diterpene diglycoside, or another non-nutritional sugar described herein, and a PWS-ED drug are disclosed, wherein the complexes significantly enhance the solubility of poorly water soluble ED drugs in vitro. The sugar-compound complexes may employ a single sugar or a combination of two or more indicated sugars. One embodiment encompasses the use of one or two sugars in a ratio of about 1 to about 10 moles of sugar per mole of drug and any value between one and ten to prepare water-soluble sugar-drug complexes. Methods for preparing such complexes and pharmaceutical compositions comprising such complexes are also disclosed.

Provided herein are methods for improving the water solubility of PWS-ED drugs by means of producing stable complexes of the drug and a sugar, wherein the stability is as defined herein. Without being bound by any theory, it is believed that the stability of these complexes is based on hydrophilic hydrogen bonds and/or host-guest chemistry between the drug and the sugar. In practice, the methods produce a stable complex between a drug for delivery (e.g., oral delivery) to a subject in need thereof and a pharmaceutically acceptable sugar form. In the case of a host-guest chemistry, the compounds join together to form a complex, wherein one of the compounds in the complex is the host and one is the guest. In some cases, in addition to hydrophilic hydrogen bonds, hydrophobic interactions such as van der Waals interactions may be involved between the drug and the sugar, which may further enhance the stability of the complex comprising the host and the guest together.

In general, this technique demonstrates that the solubility of a drug can often be improved by forming a particular salt thereof, as compared to the free form of the compound. Although such modifications may enhance the solubility of the drug, the resulting salt may still be considered poorly water soluble. Thus, the methods and complexes described herein may be useful for PWS-ED drugs in which the free base or acid or its salt form is found to be poorly water soluble.

Provided herein are complexes comprising: one or more disclosed sugars, such as diterpene diglycosides (DTG) or stevioside and stevia (examples of triterpenes); and a water-soluble erectile dysfunction (ED) drug (i.e., a poorly soluble or insoluble drug, "PWS-ED drug"), wherein the solubility of the complex is significantly enhanced compared to the PWS-ED drug alone (e.g., not present in the complex produced by the disclosed methods). In some cases, moderately soluble (less than 10 mg/mL solubility or considered poorly water soluble) compounds can be made more soluble by complexing with a sugar as defined herein in the same sugar to compound ratios as described herein. This is particularly important for solubility of compounds for topical applications because the compound is transported across the skin barrier for in vivo absorption. Alprostadil is considered to be insoluble or poorly water soluble, with a solubility of less than 1 mg/ml. Exemplary erectile dysfunction drugs include free forms of alprostadil, avanafil, sildenafil, tadalafil, and vardenafil, their pharmaceutically acceptable salts, their prodrugs, and polymorphs. The complexes described herein employ a PWS-ED drug, which is typically a pharmaceutical compound having at least one heteroatom capable of forming a hydrogen bond with DTG or a non-nutritious sugar. Without being bound by theory, it is believed that the complex formed is formed via non-covalent hydrogen bonding and, where appropriate, hydrophobic interactions, such as van der Waals forces.

As is well known, the sugar moiety DTG has a plurality of hydroxyl functional groups capable of forming hydrogen bonds. In some cases, certain sugars may also contain carboxyl groups (e.g., sialic acid, glucuronic acid, etc.), amine groups (e.g., glucosamine), or N-acetyl groups (e.g., N-acetylglucosamine), each of which is capable of forming hydrogen bonds. The presence of such functional groups allows DTG to participate in hydrogen bonding with drug compounds that contain at least one heteroatom capable of forming hydrogen bonds with DTG.

One embodiment discloses a method of improving the water solubility of a compound, the method comprising: mixing (e.g., stirring) a PWS-ED drug and a sugar in a solvent or co-solvent (e.g., 95% ethanol is a co-solvent with ethanol and water); and removing the solvent to obtain a powder composition comprising the sugar and the ED drug in a more soluble form. The embodiment encompasses a ratio of sugar to ED drug of about 1:1 to about 1:20 or about 1 to about 10 by weight and any value between these 1 to 20 ranges. For example, stevia can be used in a ratio of 3:1 stevia to compound. In another embodiment, two sugars can be used to form a complex with the ED drug, such as a combination of rubusoside and stevioside in the presence of a poorly water-soluble compound and 95% ethanol (or another solvent). For example, the ratio of ED drug: rubusoside: stevioside may be 1.0:7.4:1.0. For ED drugs that are not well soluble in water, the goal would be to keep the amount of sugar below the GRAS (FDA's Generally Recognized As Safe) recommended limit for each sugar. Another aspect encompasses the use of isopropyl alcohol as one of the solvents for topical use.

The methods disclosed herein use a solvent to dissolve the sugar and the compound or drug to generate hydrogen bonds and/or an inclusion complex capable of dissolving the compound and the sugar. In one aspect, the solvent can be ethanol, methanol, water, hexane or other pharmaceutically acceptable solvents or combinations thereof. In another aspect, the second solvent can be ethanol, methanol, water, hexane or other pharmaceutically acceptable solvents.

In one embodiment, the complex described herein can be represented by the following formula (I): [ DTG ] _pdrug (I ) wherein DTG in formula (I) is a non-nutritive sugar as defined herein, and the drug is a PWS-ED drug, and wherein p is a molar ratio of up to about 20 moles of sugar (DTG) per mole of the PSD, wherein the sugar is one or more of the following: rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, leucoside A, leucoside B, leucoside D, stevioside, stevia, n-octyl glucose, n-dodecyl-β-D-maltoside, Advantame®, numetame, thaumatin, saccharin, sucralose, steviol glycoside (steviol glycosides), glycoside), monk fruit, aspartame, acesulfame potassium or psicose, and the proviso that the water-soluble sugar-drug complex increases the water solubility of the PWS-ED drug by at least five (5) times at 20°C compared to the water solubility of the drug not in the water-soluble sugar-drug complex. p may be from about 1.0 to about 12.0 or from about 1.5 to about 10.0. Water-soluble complexes encompassed also include: compounds with poor water solubility are in the form of salts of the compounds. The complex may be formed in the presence of an acid or a base. One disclosed embodiment is a method of improving the solubility of a drug, the method comprising: mixing (e.g., stirring) the drug and a sugar in a solvent; and removing the solvent to obtain a powder composition and/or a complex comprising the sugar and the drug in their more soluble form. Embodiments encompass that the drug and sugar may be in a weight ratio of about 0.1:1.0 to about 1.0:20.0 or about 1.0 to about 10.0, and any value in units of 0.1 between the ranges of 0.1 to 20.0. For example, stevia may be used in a 3:1 ratio of stevia to drug.

As defined below, DTG defined in formula (I) may be a diterpene or triterpene glycoside or other non-nutritional sugars that can be used as natural sweeteners. Such DTGs include stevioside and rubusoside and other related compounds. One embodiment includes using non-nutritional sugars in the disclosed method to bind to the drug through hydrogen bonds and/or in complex form, wherein the sugar may be rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, leucoside A, leucoside B, leucoside D, stevioside, stevia, n-octyl glucose, n-dodecyl-β-D-maltoside, Advantame®, neotame, thaumatin, saccharin, sucralose, steviol glycosides, monk fruit, aspartame, acesulfame potassium or psicose.

The methods disclosed herein use a solvent or a co-solvent to dissolve the sugar and the PWS-ED drug. The sugar and drug used are dissolved in the solvent or co-solvent, and hydrogen bonds are generated between and among these components. When the solvent or co-solvent is removed, the remaining hydrogen bonds are between the sugar and the drug, so that the complex has better water solubility than the compound in a non-complexed form. In one aspect, the solvent can be ethanol, methanol, water, hexane, or another pharmaceutically acceptable solvent or a mixture thereof. The co-solvent can include water and alcohols, such as methanol, ethanol, or isopropanol. For example, a preferred solvent mixture includes water, methanol, and ethanol. The additional solvent can be ethanol, methanol, water, hexane, or a co-solvent, or another pharmaceutically acceptable solvent. Illustrative examples of co-solvents may include the following: about 50% to less than 100% solvent and water; or about 50% to less than 100% ethanol and the remainder methanol; or 50% to less than 100% ethanol and up to about 50% to about 0.001% methanol, and any value of methanol in that range. In another embodiment, a buffer may be used instead of water.

Another embodiment encompasses a powder formulation comprising a lyophilized powder prepared by the disclosed method, wherein the powder formulation has improved solubility due to hydrogen bonding between the sugar and the drug forming the complex. The complex has improved water solubility compared to the water solubility characteristic of the drug solubility before hydrogen bonding with the sugar. One embodiment encompasses that the weight ratio of drug to sugar of the sugar-drug complex formed by the method can be about 0.1:1.0 to about 1.0:20.0 or about 1.0:1.0 to about 1.0:20.0, and any value in units of 0.1 between 0.1 and 1:20.0. Alternatively, the compound and the sugar are in a molar ratio of about 1:1 to about 1:10, or in a molar ratio of 1:1 to 1:5, or in a molar ratio of 1:1 to 1:3, and any value in units of 0.01 between each of these ratios provided herein.

In another embodiment, a complex can be formed from two disclosed sugars, wherein the total amount of sugars used falls within the ratios discussed above. For example, a sugar-drug complex can use rubusoside and stevioside as sugars (the weight or molar ratio of rubusoside to stevioside is 1:7.5), and then this sugar mixture is combined with a drug at a weight or molar ratio of total sugar to drug of 8.5:1; or any combination of the disclosed sugars is used. In another example, the two non-nutritional sugars are in a molar ratio of sugar to drug of about 10.0:1.0 or 9.0:1, 8.0:1.0, 7.0:1.0, 6.0:1.0, 5.0:1.0, 4:0:1.0, 3.0:1.0, 2.0:1.0 or 1:1, and any value in units of 0.1 therebetween. In another embodiment, the complex may be formed from a mixture of three or more sugars.

Another embodiment encompasses a powder formulation suitable for reconstitution in water or saline, wherein when reconstituted in water, saline or buffered saline (e.g., phosphate buffered saline, PBS), the complex in the formulation renders the drug complexed with the sugar more water soluble than the drug in the absence of the sugar bound to the drug. Water, saline and buffered saline may be sterile as appropriate. The reconstituted complex, when formulated in sterile water or sterile saline, may be administered to a subject in any form suitable for administration, such as intraperitoneally (ip), intranasally, intramuscularly (im), subcutaneously (sc), sublingually, orally or buccally, with oral delivery being preferred.

In the case of oral delivery, which includes sublingual formulations, the sugar-compound may be in the form of tablets, strips, sublingual drops, sublingual sprays, buccal tablets or buccal blister tablets or sublingual tablets for rapid release, such as liquid drops, inhalation sprays or powders and nebulizer liquids. The weight ratio of the compound to the sugar for the powder formulation may be from about 1.0:1.0 to about 1.0:20.0 or from about 1.0:1.0 to about 1.0:10.0, and any value in 0.1 between 0.1 and 1:20.0. Alternatively, the compound and sugar are in a molar ratio of about 1.0:1.0 to about 1.0:10.0, or any value in 0.01 between them. In another embodiment, the water-soluble complex comprises a molar ratio of about 2 to about 5 moles of sugar per mole of the poorly water-soluble drug.

The complexation of the drug with DTG can be viewed as a donor (DTG) acceptor (drug) interaction, such as a "host-guest chemical reaction" between the drug and DTG. In practice, the complexation allows the PWS-ED drug to interact with the sugar in the chosen solvent, which essentially allows the drug to acquire the water solubility of the sugar. In addition, this acquired solubility is maintained in the upper part of the gastrointestinal tract (GI) after ingestion. Upon passage to the lower part of the GI tract, the glucose molecule on the sugar is enzymatically cleaved by endogenous bacteria in a time-dependent manner to yield the aglycone (di- or triterpenoid). See, e.g., Absorption and distribution of steviol glycosides in animal and human models . Stevia Technology. Retrieved on July 31, 2023, from the following website: https://www.steviashantanu.com/single-post/2015/11/18/absorption-and-distribution-of-steviol-glycosides-in-animal-and-human-models. Without being bound by any theory, enzymatic cleavage of the sugar groups allows the complex to deaggregate (e.g., decomplex), thereby releasing the poorly water-soluble drug. This process is slow enough that a substantial portion of the amount of drug released at any given time can be absorbed.

Disclosed herein and encompassed are water-soluble complexes comprising a sugar and a poorly water-soluble ED drug, the complex comprising: a molar ratio of up to about 5 moles of sugar per mole of the poorly water-soluble drug, wherein the sugar may be, for example, one or more of: rubusoside, dulcoside B, dodecyl-β-D-maltoside, stevioside, or leucoside A, with the proviso that the water-soluble complex increases the water solubility of the poorly water-soluble drug by at least five (5) times at 20° C. as compared to the water solubility of the drug not in the water-soluble complex; and with the further proviso that the maximum amount of the sugar in a daily unit dose of the complex does not exceed about 10 mg/kg. The sugar used to prepare the water-soluble complex may be rubusoside.

Another water-soluble complex encompasses the use of a poorly water-soluble drug (i.e., erectile dysfunction drug) selected from the group consisting of alprostadil, sildenafil, tadalafil, vardenafil, and avanafil in free form, salt form, or polymorph. In the case of alprostadil, the complex increases solubility to aid drug delivery across the skin.

In another embodiment, the water-soluble complex may be a sugar selected from the group consisting of rubusoside, leucoside A, dodecyl-β-D-maltoside, dulcoside B or stevioside or any combination or arrangement thereof.

In another embodiment, the water-soluble complex comprises a molar ratio of about 2 to about 5 moles of sugar per mole of the poorly water-soluble drug.

In another embodiment, the water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of sugar per mole of the poorly water-soluble drug. In another embodiment, the water-soluble complex comprises a molar ratio of about 3 moles of sugar per mole of the poorly water-soluble drug. Another embodiment encompasses that the water-soluble complex is stable for at least about 2 hours when dissolved in water at pH 8.5.

In another embodiment, the water-soluble complex is stable for at least about 2 hours when dissolved in water at pH 4. In some cases, the water-soluble complex should be stable for at least 2 hours at a pH of about 1.5 to about 2.0.

Another embodiment encompasses that the dry form of the water-soluble complex is stable at 30°C for at least 90 days.

Another embodiment encompasses the water-soluble complex in the form of a powder, tablet, orally disintegrating tablet, chewable (e.g., gel) capsule, liquid, gel, film, lozenge, effervescent powder or tablet, emulsion, or formulated for parenteral administration. Alternatively, the water-soluble complex may be a formulation prepared for parenteral administration for topical, intradermal, intranasal, subcutaneous, or intramuscular administration. Another embodiment encompasses formulating the water-soluble complex into a film, effervescent powder or tablet, syrup, solution, elixir, emulsion, chewing gum, lollipop, sublingual drops, soft gel, or tincture.

Another embodiment encompasses a water-soluble complex comprising a sugar and a poorly water-soluble drug, the water-soluble complex comprising: a molar ratio of about 3 moles of sugar per mole of the poorly water-soluble drug, wherein the sugar is one or more of: rubusoside, leucoside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; wherein the water-soluble complex is stable at pH 8.5 and pH 8.5. 4.0 for at least 2 hours (or in some cases, the water-soluble complex should be stable in water at a pH of about 1.5 to about 2.0 for at least 2 hours); with the proviso that the water-soluble complex increases the water solubility of the poorly water-soluble drug at 20° C. by at least five (5) times as compared to the water solubility of the poorly water-soluble drug not in the water-soluble complex; and with the proviso that the maximum amount of the sugar in a daily unit dose of the water-soluble complex does not exceed about 280 mg.

Another aspect encompasses a method for preparing a water-soluble complex comprising a sugar and a poorly water-soluble drug, the method comprising the steps of: blending a sugar and a poorly water-soluble drug in a molar ratio of about 2 to about 5 moles of the sugar per mole of the poorly water-soluble drug in at least 85% ethanol until dissolved, thereby forming a 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 the following: rubusoside, leucoside A, dulcoside B, dodecyl-β-D-maltoside (DDM) or stevioside; and wherein the blending step is optionally carried out under a pharmaceutically acceptable acid; and optionally drying the water-soluble complex. Another method encompasses the sugar used in the method being rubusoside or stevioside. The poorly water-soluble drug used in the method for preparing the water-soluble complex can be one or more of the following: sildenafil, tadalafil, vardenafil, avanafil, alprostadil or a pharmaceutically acceptable salt of any one of them. The method can further include drying the water-soluble complex to form a solid. The dried solid can be redissolved in a suitable liquid. In the case of alprostadil, the formulation of alprostadil and sugar covered by the composite herein is only used for local use.

The method for preparing the water-soluble complex may further require the presence of a pharmaceutically acceptable acid, base or buffer to be added during the mixing step, in the presence of a sufficient amount of the pharmaceutically acceptable acid to dissolve the reaction mixture and make it homogeneous or clear. The pharmaceutically acceptable acid used in the method may be acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic 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.

The method of preparing a water-soluble complex may be blended at a molar ratio of about 2 to about 5 moles of the sugar per mole of the poorly water-soluble drug. The sugar may be rubusoside or stevioside. Alternatively, the water-soluble complex prepared by the method may have a molar ratio of about 2 to about 4.5 moles of sugar per mole of the poorly water-soluble drug. In another embodiment, the water-soluble complex formed from the method may contain a molar ratio of about 3 moles of sugar per mole of the poorly water-soluble drug.

Exemplary methods include drying dissolved sugars and poorly water-soluble compounds to obtain a water-soluble sugar-drug complex, dissolving the dried water-soluble sugar-drug complex in a second solvent, and filtering the dissolved water-soluble sugar-drug complex to provide a clear aqueous solution of the complex.

These and other embodiments that will become apparent to those skilled in the art after reading this specification provide improvements in patient compliance, satisfaction, comfort, and overall treatment experience.

Related applications

This application claims the benefit of U.S. Provisional Application Nos. 63/517,600, 63/481,050, 63/443,546, and 63/459,761, filed on August 3, 2023, January 23, 2023, February 6, 2023, and April 17, 2023, respectively; the contents of each of which are incorporated herein by reference in their entirety.

Creating new means to enhance compounds that are poorly water soluble or that are inadequately delivered orally, for example due to unacceptable taste or consistency, to form water soluble complexes has significant implications in many fields, including pharmacology, animal care, food supplements, animal feed, and the like. Complexes formed using the methods herein can assist compounding pharmacies in compounding patient-specific amounts of active compounds and in compounding active compounds into palatable formulations for any individual. Without being limited by any theory, the proposed sugar-drug combinations can be produced by hydrogen bonding or by host-guest chemical reactions to form complexes, where two compounds are in a complex and one compound has a cavity that can accommodate a "guest" compound. The interactions between the host and the guest in the complex can include hydrophobic interactions, such as van der Waals interactions. Nevertheless, in this sugar-compound form, the complex formed by the sugar-compound increases the solubility of the compound in water relative to the individual compounds. The complex also imparts a sweeter taste, rather than the bitter or acrid taste imparted by many compounds in free form or in salt form. This sweeter taste will have benefits by contributing to a sweeter and more palatable taste when the drug is administered to a patient.

Water-soluble sugar-ED drug complexes are also designed to improve the amount of drug delivered ( _Cmax ) and/or the duration of drug delivery over time at therapeutic amounts. The basic theory is that when the complex enters the large intestine, the release of the drug will depend on the presence of enzymes and/or conditions that degrade the sugars around the drug. Since the rate at which the complex enters the large intestine will be slow and also include other materials, and since the sugar to drug ratio of each complex is likely to be a Gaussian curve, with some complexes having higher sugar ratios than others, the release rate will be extended to allow sufficient amount of drug released from the sugar and thus prolonged delivery to the liver over time. As the ratio of sugar to complex drug increases, the duration of drug release should also increase. Thus, the use of such complexes allows for a sustained release which in turn is associated with inhibiting drug overload relative to the delivery mechanism that may occur when the drug is not administered as part of the complexes described herein. This in turn will provide a higher _Cmax and longer duration of effective concentration of the drug.

The following definitions provide guidance for the interpretation of a term, unless the context of its appearance elsewhere in this specification indicates otherwise.

By using a powder or liquid formulation, it is easier to administer the proper dose, reducing errors, variations, and waste caused by variations in pill splitting technology. Another benefit achieved by the method and the products produced by the method is a reduction in the amount of active drug because of greater solubility and, therefore, greater bioavailability. The method provides a cost benefit in that fewer resources must be utilized to obtain less active compound, but still achieve the desired patient outcomes.

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 the event or circumstance does not occur.

As used herein, the term "about" when used before a numerical value designation, such as temperature, time, amount, concentration, and the like (including ranges), indicates an approximate value that can vary by (+) or (-) 15%, 10%, 5%, 1%, or any sub-ranges and/or values therebetween. When used in relation to a dosage, the term "about" means that the dosage can vary by +/- 10%. The term "about," when used to modify an amount of a substance or composition (e.g., kg, L, or equivalent), a value of a physical property, or a value of a parameter characterizing a processing step (e.g., the temperature at which a processing step is performed), or the like, refers to the amount of variation in the numerical value that may occur, for example, through typical measurements, handling, and sampling procedures involved in preparing, characterizing, and/or using the substance or composition; through inadvertent errors in such procedures; through differences in manufacture, source, or purity of ingredients used to prepare or use the composition or perform the process; and the like. In certain embodiments, "about" may 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%.

As used herein, the term "comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements but not excluding other elements.

As used herein, "consisting essentially of" when used to define compositions and methods shall mean that no other elements of any essential significance are included in the composition for the stated purpose. Thus, a composition consisting essentially of the elements defined herein or a method consisting essentially of the steps defined herein will not exclude other materials that do not materially affect the basic and novel characteristics of the claimed subject matter.

As used herein, the term "consisting of" shall be meant to exclude other ingredients or substantial process steps beyond trace elements. Embodiments defined by each of these transitional terms are within the scope of the present disclosure.

The weight ratio of the sugar to the compound in the formulation may range from about 0.1:1, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1 and 20.0:1.0, and any value in increments of 0.1 therebetween. Alternatively, the ratio may be about 1.0:0.001 and about 20.0:1.0.

The "mole ratio" or "molar ratio" of sugar to compound can range from 1.0 to 0.001 or from 10.00 to 0.1, and any value in 0.01 between those two ranges. The "molar ratio" of "sugar to drug compound" in the formulation can range from about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or up to about 10:1, and up to about 20:1, and any value in 0.1 between. Alternatively, the sugar to drug compound ratio can be from about 1.00:1.00 to about 5.00:1.00, and any value in 0.01 between the ranges. In one embodiment, a sugar to PSD molar ratio of about 2.0 to about 1.0 is used.

The term "sugar" used means that the sugar is a non-nutritive sweetener. The sugar or "DTG" used herein may be rubusoside, dulcoside B (also known as leucoside C), stevia, leucoside A (also known as stevioside A3), stevioside (also known as diterpene glycoside and having a chemical formula of C ₃₈ H ₆₀ O ₁₈ ), n-octylglucose, n-dodecyl-β-D-maltoside (also known as dodecyl maltoside or lauryl maltoside), stevia (having a chemical formula of C ₄₄ H ₇₀ O ₂₃ ), and steviol glycosides (such as steviol glycosides derived from Stevia rebaudiana ). Although other steviosides are known, only those sugars approved by the FDA GRAS are covered. Preferably, the sugar is one or more of rubusoside, stevia, dulcoside B, stevioside, n-dodecyl-β-D-maltoside or leucoside A, which can be used in any combination or arrangement. Any arrangement of the six sugars listed (two of the sugars, three of the sugars, etc.) is also contemplated. In addition, the price of the sugar is a factor in whether the sugar is a good commercial sugar for dissolving poorly water-soluble or insoluble drugs.

"ED compound", "ED drug compound", "poorly water-soluble ED compound" or "PWS-ED drug compound" means an ED drug compound, wherein the drug compound is poorly water-soluble or insoluble (e.g., a poorly water-soluble drug, PSD, also includes a poorly water-soluble compound). A "poorly water-soluble ED drug or compound" is a compound whose commercial utility is lacking or compromised due to its inadequate water solubility. Impaired commercial utility includes attempts to improve solubility, including but not limited to, good drugs that are generally considered to lack solubility, demonstrated by the use of nanotechnology, the use of prodrugs, the use of non-aqueous solvent delivery, and the like. The term "insoluble" is often applied in this technique to compounds that are poorly or very poorly soluble in water (see, e.g., Savjani et al. "Drug Solubility: Importance and Enhancement Techniques," ISRN Pharm. 2012, doi: 10.5402/2012/195727). In general, a compound is considered "poorly soluble" in water when less than about 1 mg/mL of a poorly soluble compound can be dissolved across the physiological pH range at 20°C (see, e.g., C. Moreton , "Poor Solubility - Where do we stand 25 years after the 'Rule of Five'?" Amer . Pharm . Rev. (2021). Without being bound by theory, the drug compound preferably has available hydrogen bonding sites to form such bonds with the sugar and/or for the compound and the sugar to form a complex. The exemplary drugs mentioned herein are also intended to include their salt forms, their polymorphs, their free forms or their metabolites or prodrugs (prodrugs). "Compound" or "drug compound" or "poorly soluble drug" is a drug compound in which the The drug compound is poorly soluble or insoluble in water (e.g., a poorly soluble drug, PSD). Without being bound by theory, the drug compound preferably has available hydrogen bonding sites to form such bonds with a sugar and/or for the compound and the sugar to form a complex. For the compounds and methods described herein, the PSD is an erectile dysfunction drug, such as sildenafil (or desmethylsildenafil) or sildenafil hydrocitate (SLC) thereof. (which is sold under the brand names Viagra® and Revatio®) or other pharmaceutically acceptable salts (e.g., lactate or nitrate); tadalafil or its pharmaceutically acceptable salt (sold under the brand names Cialis® and Adcirca), or crystalline forms, such as those described in U.S. Publication No. 2006111571; vardenafil or its pharmaceutically acceptable salt (vardenafil hydrochloride, brand names Levitra® or Staxyn®) or other salt forms (e.g., anhydrous hydrochloride, hydrochloride trihydrate, hydrochloride); and avanafil or its pharmaceutically acceptable salt (brand name Stendra®). The properties of the drugs are provided in the following table: Table PSD Compound Name IUPAC Name Solubility Molecular formula Molecular weight Avanafil 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[( 2S )-2-(hydroxymethyl)pyrrolidin-1-yl] -N- (pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide Soluble in DMSO (97 mg/ml at 25°C); methanol; water (<1 mg/ml at 25°C); and ethanol (<1 mg/ml at 25°C) C ₂₃ H ₂₆ ClN ₇ O ₃ 483.9 g/mol Sildenafil 5-[2-ethoxy-5-(4-methylpiperidin-1-yl)sulfonylphenyl]-1-methyl-3-propyl- 6H -pyrazolo[4,3-d]pyrimidin-7-one Solubility in water: As sildenafil citrate, 3.5 mg/mL C ₂₂ H ₃₀ N ₆ O ₄ S 474.6g/mol Tadalafil (2 R ,8 R )-2-(1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.0 ^{3 , 8} .0 ^{11 , 16} ]heptadeca-1(10),11,13,15-tetraene-4,7-dione In water at 25°C, 220 mg/L C ₂₂ H ₁₉ N ₃ O ₄ 389.4 g/mol Vardenafil 2-[2-ethoxy-5-(4-ethylpiperidin-1-yl)sulfonylphenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4-one 3.5 mg/L/estimated/in water at 25℃ C ₂₃ H ₃₂ N ₆ O ₄ S 488.6 g/mol Alprostadil 8000 μg/100 mL distilled water; it is almost insoluble in ethanol, ether and ethyl acetate. C ₂₀ H ₃₄ O ₅ 354.481 g/mol Poorly water-soluble drugs are compounds that dissolve no more than about 100 μg/mL at 20-25°C. Moderately soluble drugs (having a solubility of less than 10 mg/mL) are those in which less than 10 mg of the compound can be dissolved in water and preferably less than 5 mg of the compound can be dissolved in one milliliter of water. In the case of moderately water-soluble sildenafil, a complex may be formed between it and the sugars described herein for the purpose of enhancing topical transport across the skin barrier. In the case of alprostadil, a poorly water-soluble ED drug, increasing water solubility may improve transport across the skin barrier.

A "stable" sugar-ED compound is a water-soluble complex (i.e., [ DTG ] _pdrug ) prepared by the methods described herein, which can be prepared and isolated, and whose structure and properties remain substantially unchanged or can be caused to remain substantially unchanged for a sufficient period of time to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject). As described elsewhere, DTG may also be replaced by one of the other sugars listed herein. Another feature that can be imparted by methods that improve the solubility of a drug/compound is the ability to increase the storage stability of the sugar-compound. For example, the complex formed by the described methods produces a sugar-compound complex that is stable for at least about 2 hours when dissolved in water at pH 8.5. Additionally or alternatively, the water-soluble sugar-drug complex is stable for at least about 2 hours when dissolved in water at pH 4, and in some cases at a pH of about 1.4 to 1.6 for at least about 2 hours. Additionally or alternatively, the water-soluble complex in dry form is stable for at least 90 days at 30°C. Additionally or alternatively, the complex formed by the described methods forms a dry complex that does not require refrigeration and is stable at room temperature for at least 24 hours. The water-soluble complex formed by the methods described herein provides for an increase in the water solubility of the poorly water-soluble drug by at least five (5) times at 20°C compared to the water solubility of the poorly water-soluble drug not in the water-soluble complex; and further provided that the maximum amount of the sugar in the daily unit dose of the water-soluble complex does not exceed about 280 mg.

The method dissolves the compound in ethanol in the presence of a sugar, followed by drying or evaporating (e.g., freeze drying or lyophilization or other means of evaporating ethanol from the mixture) the liquid in the composition. Lyophilization generally requires prefreezing the complex, followed by primary and secondary drying steps. The remaining residue, comprising the hydrogen-bonded and/or sugar-compound complex, can then be formulated into solid forms for oral, sublingual or buccal administration, such as pills, capsules, caplets, chews (e.g., soft candies or gums), tablets, lozenges and soft gels. Water-soluble drug complexes (e.g., hydrogen-bonded and/or included complex sugar-compounds) may also or alternatively be formulated as suppositories, lotions, gels, and/or ointments. Water-soluble drug complexes may also be formulated as inhalable powders. Water-soluble complexes may be formulated into suitable topical forms. In another aspect, the water-soluble complex may be formulated into an injectable liquid for topical injection into an individual via inhalation, subcutaneous (SC), or administered in the form of a patch, or in the form of a hydrogel for intraperitoneal (IP) and intramuscular (IM) administration. For example, sildenafil citrate has been formulated as a microemulsion-loaded hydrogel as a means of delivering sildenafil to the penis and its local cellular metabolic machinery. In one example, sildenafil citrate is formulated into a microemulsion system using isopropyl myristate, Tween 80, PEG400, and water (30:20:40:10); the hydrogel used in the microemulsion is 2% w / w poloxamer 188 (Atipairin et al., "Development of a sildenafil citrate microemulsion-loaded hydrogel as a potential system for drug delivery to the penis and its cellular metabolic mechanism," Pharmaceutics 12(11): 1055 (2020)). Alternatively, transdermal patches can be prepared using nanotechnology to deliver sildenafil. Delivery can be performed in combination with a transdermal enhancer (see, for example, WO2014152382). Sildenafil has also been formulated as a 3.6% cream. The use of surfactants, such as poloxamers (e.g., P188), T20 or T80, to help dissolve sugars and PSD is contemplated herein. The surfactant can be used alone with sugars and PSD or further combined with a pharmaceutically acceptable solvent, acid, base or buffer or a combination thereof.

Alternatively, the lyophilized water-soluble complex can be formulated into a liquid formulation for administration, such as in a metered nasal spray, inhalation mist, eye drops, or by aerosol administration by the patient. Additionally or alternatively, the lyophilized water-soluble aggregate can be formulated into a food additive or an additive in animal feed. The PSD must be a PSD that can be completely or partially dissolved in 95% ethanol, 50% or a greater proportion of ethanol in water (e.g., 50%, 55%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94% and 95% spectrophotometric grade ethanol) in the presence of sugar. Preferably, the PWS-ED drug with a pharmaceutically acceptable acid and the sugar, as appropriate, are dissolved in at least about 85% ethanol. Optionally, the water-soluble aggregates remain soluble without forming a precipitate for at least 24 hours after formation.

When necessary, polyethylene glycol (PEG) can be added to liquid and powder formulations to further improve bioavailability. Typically, PEG is between 2000 and 6000 Daltons, between 3000 and 4500 Daltons, or between 3200 and 3700, as well as other pharmaceutically acceptable molecular weights utilized when PEG is formulated with a compound. Popular commercially available PEG forms have molecular weights of 3350, 4000, and 6000 Daltons. The preparation of PEG can be, for example, polydisperse or monodisperse. If it is polydisperse, the molecular weight describes the weighted average molecular weight of the preparation. Depending on the formulation in powder or liquid form, the weight ratio of PEG to the compound can vary between 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1 and include the range. In one embodiment, the weight ratio is about 8:1.

For administration, the powder form can be reconstituted in a liquid vehicle, either at the manufacturing site, at the dispensing pharmacy, or by the patient. The liquid vehicle can be water, a buffered aqueous solution, a syrup, or a drinking water, such as an energy drink or an electrolyte-rich drink. For example, a sugar-compound with improved solubility can be reconstituted into, for example, sterile saline or another sterile liquid carrier for administration to a subject in the form of eye drops or via the subcutaneous (s.c.), intranasal, intraperitoneal (i.p.), intramuscular (i.m.), or oral routes (oral into the gastrointestinal tract or buccal or sublingual administration). The sugar-compound can also be formulated as a metered nasal spray or delivered by subcutaneous or intramuscular injection.

For some poorly water-soluble compounds, it may be necessary to use a surfactant (e.g., Tweens such as T20, T60, T80, T85 or poloxamers such as P188 and P407) to enhance the solubility of one or more sugars and compounds in a solvent or solvent mixture. Any surfactant used in this manner must be capable of surface and interfacial tension measurements.

Suitable ingredients for formulating a water-soluble aggregate in a tablet or pill or another solid oral form may include, for example, any or all of corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, and hydroxypropyl methylcellulose. Additional compositions of the described complexes may include a former, an oral stool softener, an oral irritant, and/or a rectal suppository.

Although water-soluble aggregates dissolve slowly enough to allow the drug to enter the small intestine without settling in the stomach, other means of extending drug release are known, such as coating enteric coated tablets, which additionally coat the aggregates with a slowly dissolving polymer, where the polymer can be selected based on the desired length and/or thickness, which can alter the drug release rate; placing the aggregates in gelatin capsules; placing the aggregates in an insoluble matrix (e.g., Slow-K or Imdur Durules); placing the aggregates in an erodible matrix (e.g., MST Continus, Phyllocontin Continus); and/or enclosing the aggregates in a semipermeable membrane. See, e.g., "Pharmaceutical Issues when Crushing, Opening or Splitting Oral Dosage Forms" by the Royal Pharmaceutical Society, June 2011. Other extended release oral dosage forms include: "extended release drugs", where the dosage form of the aggregate allows for at least two times less frequent dosing than the drug aggregate in a non-extended release form. Examples of extended release dosage forms include controlled release, sustained release and/or long acting drugs. Another type of extended release oral dosage form is a delayed release drug. In an extended release form, the total dosage form releases one or more discrete portions of the drug aggregate over a given time, rather than immediately after administration. Enteric coated dosage forms are common extended release products (e.g., enteric coated aspirin and other NSAID products). Another extended release oral form of aggregates covered is a targeted release drug. A total dosage form that releases the complex at and/or near the intended physiological site of action. Another sustained release oral dosage form of the aggregate is an orally disintegrating tablet (ODT) or equivalent. ODTs have been developed to disintegrate rapidly in saliva after oral administration. The complex in ODT form can be used without the addition of water. Water-soluble aggregates disperse in saliva and are swallowed with little or no water.

As used herein, "sugar-compounds" or "hydrogen-bonded sugar-compounds" are the same and are formed using the disclosed methods. Without being bound by theory, sugar-compounds may have hydrogen bonds that are created between sugars and compounds, thereby forming a complex. In all cases where "sugar-compounds" are used, they are interpreted as including hydrogen bonds and/or being in complex form through van der Waals forces. The term "sugar" used means that the sugar is a non-nutritive sweetener. As used herein, non-nutritive sweetener sugars or "DTG" may be rubusoside, dulcoside B (also known as leucoside C), stevia, leucoside A (also known as stevioside A3), stevioside (having a chemical formula of C ₃₈ H ₆₀ O ₁₈ ), n-octylglucose, n-dodecyl-β-D-maltoside (also known as dodecyl maltoside or lauryl maltoside), stevia (having a chemical formula of C ₄₄ H ₇₀ O ₂₃ ), and steviol glycosides (such as steviol glycosides derived from stevia). Although other steviosides are known, only those sugars approved by the FDA GRAS are covered. Preferably, the sugar is one or more of rubusoside, stevia, dulcoside B, stevioside, n-dodecyl-β-D-maltoside or leucoside A, which can be used in any combination or arrangement. Any arrangement of the six sugars listed (2 of the sugars, 3 of the sugars, etc.) is also contemplated. In addition, the price of the sugar is a factor in whether the sugar is a good sugar commercially for dissolving poorly water-soluble or insoluble drugs. Exemplary sugars used to prepare the "sugar-compound" are rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, leucoside A, leucoside B, leucoside D, stevioside, stevia, n-octylglucose or n-dodecyl-β-D-maltoside, with the proviso that when the sugar is rubusoside, the compound is not praziquantel. Exemplary sugars are diterpene diglycosides (DTG) and triterpene glycosides. Without being bound by theory, it is believed that after aggregation (e.g., complexation) of DTG and PSD, a stable aggregate (e.g., complex) may be generated by non-covalent hydrogen bonding and, if appropriate, hydrophobic interactions (e.g., van der Waals forces). The term "sugar" as used herein refers to a non-nutritive sweetener. Sugar used herein may be dulcoside A, sucrose, D-fructose, sucralose, leucoside B, leucoside D, stevia, n-octylglucose, Advantame®, neotame®, thaumatin, saccharin, monk fruit, aspartame, acesulfame potassium (Ace-K), psicose, rubusoside, dulcoside B (also known as leucoside C), leucoside A (also known as stevioside A3), stevioside, n-octylglucose and steviol glycosides (such as steviol glycosides derived from stevia). Although other steviosides are known, only those steviosides approved by FDA GRAS or approved for use in Europe are included. Preferably, the sugar is one or more of rubusoside, stevia, dulcoside B, stevioside or leucoside A, which can be used in any combination or arrangement. Any arrangement of the six sugars listed is also contemplated (two of the sugars, three of the sugars, etc.). In addition, the price of the sugar is a factor in whether the sugar is a good commercial sugar for dissolving poorly water-soluble or insoluble drugs. Additional contemplated sugars that are not DTG sugars but that may be paired with the PSDs described herein include: Advantame® - an aspartame analog; N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-aspartoyl]-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 causes insulin spikes. Neotame ® - Trademarked as Newtame®, and is a derivative of aspartame, which is classified as an aspartame-derived dipeptide. Neotame® has a low glycemic index (GI) and zero calories, but causes an insulin spike. Thaumatin - Also known as TALIN®, Soma sweet. It is a mixture of the sweet tasting proteins Thaumatin I and Thaumatin II from the West African bamboo taro ( Thaumatococcus danielli ). Saccharin - Also known as cyclamate or benzylsulfonimide, and is in the form of salts such as saccharin sodium and saccharin calcium. It is marketed 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 causes an insulin surge. Sucralose - sold under the name Splenda and is an organochlorine sweetener with the chemical name 1,6-dichloro-1,6-dideoxy- β - D -fructofuranosyl-4-chloro-4-deoxy- α - D -pyranoside (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 causes an insulin surge. Lou Han Guo - also known as Siraitia grosvenorri ), the immortal fruit, the longevity fruit, and the monk fruit (luohan guo), from which a calorie-free sweetener can be obtained. The FDA calls this sweetener monk fruit extract (SGFE). The compound that produces the sweetness is the monk fruit glycoside, which has a monk fruit alcohol backbone and glucose units (glycosides) attached to it. It is sold under the brand name Monk Fruit as Raw®, Lakanto®, PureLo®, SPLENDA® monk fruit sweetener, SweetLeaf®, and Whole Earth®. SGFE does not appear to raise blood sugar levels. Aspartame - sold under the names Nutrasweet, Equal, and Sugar Twin and does contain calories. The chemical name is L-aspartame-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 causes an insulin surge. Acesulfame potassium - Also known as Ace-K and sold under the brand names Sweet One® and Sunett®. Ace-K has a low glycemic index (GI) and zero calories, but causes an insulin surge. Allulose - is a sugar found naturally in figs and raisins. It is also known as D-psicose/D-allulose and has very few calories. It does not affect insulin or blood glucose 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.

The sweetness of sugar is compared to table sugar (sucrose) and summarized in the following table (obtained from the U.S. FDA): sugar Compared with the sweetness of sucrose Advantame® 20,000 Neotame® 7,000-13,000 Thaumatin 2,000-3,000 saccharin 200-700 Sucralose 600 Stevioside 200-400 Luo Han Fruit 200-250 Aspartame 200 Acesulfame Potassium (Ace-K) 200

A "stable" sugar-compound is a water-soluble complex prepared by the methods described herein (i.e., a [ DTG ] _p drug ) that can be prepared and isolated and whose structure and properties remain or can be caused to remain substantially unchanged for a sufficient period of time to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

Any of the components may be packaged in a kit, packaged separately in separate containers, or mixed with one another. The end user may reconstitute the components with the included diluent or with a diluent of his or her choice. In addition to the separate or mixed components, the kit may also contain instructions for use, mixing and/or administration tools, storage containers, etc.

The terms "patient" and "subject" include animal patients or animal subjects, but preferably humans. Patients and subjects can be treated with the complexes disclosed herein or compositions comprising the described complexes. Suitable patients can be human males suffering from a condition that causes erectile dysfunction.

The term "pharmaceutically acceptable salt" refers to a salt (including internal salts, such as zwitterions) that has similar effectiveness to the parent compound and is not biologically or otherwise undesirable (e.g., neither toxic nor harmful to its recipient). The term "salt" as used herein means any of the following: acidic salts formed with inorganic acids and/or organic acids and alkaline salts formed with inorganic bases and/or organic bases. However, the compositions/compounds described herein are drug compounds in the form of sugars. The drug or compound to be complexed with sugars may be in the form of a salt of the drug or compound or in the form of a pure compound. The drug salt form may allow the salt component to occupy the binding site of the sugar, so if the compound lacks an appropriate binding site, it may be important to use a salt or free form to form a complex. "Pharmaceutically acceptable salt" means a salt used in a drug product approved by the U.S. FDA or the European Medicines Agency (EMA). The purpose of the pharmaceutically acceptable salt used in the methods described herein is to improve the solubility of sugars and insoluble drugs.

"Pharmaceutically acceptable acids" used to dissolve the compound 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 (caproic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclohexylaminosulfonic acid (cyclamic acid) acid); dodecylsulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentianic acid; glucoheptanoic acid (D); gluconic acid (D); glucuronic acid (D); glutaric acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; tartaric acid; lactic acid (DL); lactobionic acid; dodecanoic acid ; cis-butenedioic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; niacin; nitric acid; oleic acid; oxalic acid; palmitic acid; bis(hydroxynaphthoic acid); phosphoric acid; propionic acid; pyroglutamine (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid ( p ); and undecenoic acid. See, e.g., PH Stahl and CG Wermuth, eds., Handbook of Pharmaceutical Salts Weinheim/Zürich: Wiley-VCH/VHCA, 2002.

Examples of bases, including pharmaceutically acceptable bases, include sodium hydroxide, zinc hydroxide, calcium carbonate, potassium hydroxide, lithium hydroxide, anodic hydroxide, magnesium hydroxide, barium hydroxide, calcium hydroxide, strontium hydroxide, and potassium hydroxide. Other bases include trimethylamine, methylamine, aniline, and pyridine. Buffers may also be used instead of acids or bases to dissolve compounds and sugars. Exemplary buffers include bicarbonate solutions, carbonate solutions, and sodium phosphate (pKa 2.1, 7.2, and 12.3).

For embodiments of the methods of dissolving compounds or sugars described herein, the temperature of the compound, sugar, and solute can range from about 15°C to about 60°C, typically about 5°C to about 10°C from room temperature. Exemplary ranges are between about 20°C to 35°C or between about 20°C to 30°C.

The phrase "pharmaceutically acceptable composition" means a composition comprising a water-soluble complex formed by a sugar and an erectile dysfunction drug, and one or more of a carrier, a shaping agent (e.g., gelatin, cellulose, a cellulose derivative, polyvinylpyrrolidone, starch, sucrose and PEG), a stabilizer (e.g., glycine, vitamin E, carboxymethylcellulose, sodium lauryl sulfate), a thickener, and a further sweetener. The composition may be in solid or liquid form.

"Improved solubility" of a compound means that after a process of dissolving the compound in ethanol or aqueous ethanol in the presence of a sugar, the solubility of the compound without the addition of sugar is improved. After dissolving the sugar and the compound in ethanol or aqueous ethanol, the ethanol is evaporated, for example, under a high rotary vacuum. The powder obtained from the evaporation step is then redissolved (dissolved) in water. Another solvent may be methanol at 80% methanol, 95% (ACS grade) or a greater proportion (up to 100% methanol) and a combination of methanol and ethanol or methanol and water. After dissolving the sugar and the compound in ethanol or aqueous ethanol, the ethanol is evaporated, for example, under a high rotary vacuum. The powder obtained from the evaporation step is then redissolved (dissolved) in water. Improved water solubility is measured at about 20°C as described above.

The terms "water-soluble complex", "water-soluble drug complex", "water-soluble sugar-drug complex" and "water-soluble sugar-ED drug complex" mean that a sugar (e.g., rubusoside, stevia, dulcoside B, stevioside, n-dodecyl-β-D-maltoside, leucoside A or other indicated sugars discussed herein) and the poorly water-soluble erectile dysfunction drug discussed herein are included in the complex. The described method of obtaining the ED drug-sugar complex can be formed by dissolving the complex with anhydrous ethanol (100%) or 95% ethanol, optionally with a pharmaceutically acceptable acid, and further dissolved in the presence of a pharmaceutically acceptable acid, base or buffer as appropriate. The compound or drug may be any free form of the ED drug or a salt, hydrate or polymorph thereof, or a salt that is completely or partially soluble in 95% ethanol or 100% ethanol (absolute ethanol), 50% ethanol or methanol or greater (50%, 55%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% spectrophotometric grade ethanol or absolute ethanol) in aqueous ethanol. The ethanol in the dissolved sugar and ED drug is removed, and the powder is then redissolved in water to a greater extent than the drug when not in complex form. Optionally, the stability of the hydrogen-bonded complexed sugar-compound complex to remain soluble can be assessed up to 24 hours after dissolution. The term "aggregate" as used herein is meant to include aggregation or complexation, wherein complexation may further include multiple complexations to form aggregates. The compound may be in the form of a salt, an acid or a base of the compound. A method of improving the water solubility of a compound involves obtaining the compound and dissolving it in about 70% to 95% ethanol in the presence of a sugar. The weight ratio of the compound to the sugar may be about 0.1:1.0 to about 1.0:1.0, about 1.0:1.0 to about 1.0:10.0 or 1.0:20.0 and any value in units of 0.1 between about 0.1 and about 20.0.

"Daily unit dose" means the total amount of the compound administered to an individual per day, whether in a single or multiple administrations, and when a single administration is used, whether one or more pills, capsules, tablets or other formulations may be used. A dose of a formulation comprising the compound (e.g., as a water-soluble complex) will contain no more than the generally recognized as safe (GRAS) amount of any component of the formulation. For example, where steviol is used as DTG, the dose will provide no more than about 10 mg/kg of steviol, because for an average male weighing 70 kg, exceeding this dose will result in a single dose of about 700 mg of sugar. In another embodiment, the dose will provide no more than 5.0 mg/kg of steviol (or other non-nutritional sugar) to the individual. Also encompassed are steviol in amounts of about 2.0 mg/kg, 3.0 mg/kg, 4.0 mg/kg and 6.0 mg/kg per dose.

Another feature that can be conferred by the method of improving the solubility of a drug/compound by hydrogen bonding the drug/compound to a sugar is the ability to increase the storage stability of the sugar-compound.

The water-soluble sugar-drug complex can be mixed with other pharmaceutically acceptable excipients that are pharmaceutically acceptable and compatible with the active ingredient in the drug. Suitable pharmaceutically acceptable excipients include water, saline, dextrose, glycerol and ethanol or a combination thereof. Intravenous vehicles used to deliver water-soluble complexes include fluids and nutrient supplements, electrolyte supplements, such as those based on Ringer's dextrose solution and the like. Aqueous carriers used in liquid formulations containing water-soluble complexes include water, alcohol/aqueous solutions, emulsions or suspensions, including saline or buffered media. Pharmaceutically acceptable carriers for parenteral administration include sterile, aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous parenteral vehicles for the delivery of water-soluble complexes include sodium chloride solution, Ringer's dextrose solution, dextrose and sodium chloride, lactated Ringer's solution, or fixed oils.

The water-soluble complex can be mixed with other pharmaceutically acceptable excipients that are pharmaceutically acceptable and compatible with the active ingredients in the drug. Suitable pharmaceutically acceptable excipients include water, physiological saline, dextrose, glycerol and ethanol or a combination thereof.

The stable complexes disclosed herein optionally have the chemical formula of Formula (I) and Formula (II) described in the methods described herein. The stable complexes can be prepared and isolated, and their structure and properties remain substantially unchanged for a sufficient period of time, or can be made to remain substantially unchanged for a sufficient period of time to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject). As described elsewhere, DTG can also be replaced by one of the other sugars listed herein. Another feature that can be imparted by the method of improving the water solubility of the drug/compound is the ability to increase the storage stability of the sugar-compound. For example, the sugar-drug complex formed by the described method produces a sugar-compound complex that is stable for at least about 2 hours when dissolved in water at pH 8.5. Additionally or alternatively, the water-soluble sugar-drug complex is stable for at least about 2 hours when dissolved in water at pH 4, or in some cases at a pH of at least about 1.4 to 1.5 to 1.6 for at least about 2 hours. Additionally or alternatively, the water-soluble sugar-drug complex in dry form is stable for at least 90 days at 30° C. Additionally or alternatively, the sugar-drug complex formed by the described method forms a dry complex that does not require refrigeration and is stable at room temperature for at least 24 hours. The water-soluble sugar-drug complex formed by the method described herein is designed to increase the water solubility of the poorly water-soluble drug by at least five (5) times at 20° C. compared to the water solubility of the poorly water-soluble drug not in the water-soluble sugar-drug complex; and with the further proviso that the maximum amount of the sugar in a daily unit dose of the water-soluble sugar-drug complex does not exceed about 280 mg.

The water-soluble complex may optionally include preservatives and/or additives. Contemplated preservatives and additives for use with the water-soluble complex may include antimicrobial agents, antioxidants, chelating agents, inert gases, and the like. The preservatives and/or additives are blended with the water-soluble complex after the complex is formed.

The phrase "poorly water-soluble ED drug", "PSD", "PWS-ED drug" or "drug compound" means an ED candidate drug or a regulatory-approved ED drug that has a water solubility of no more than 10 mg/mL in distilled water alone. A regulatory-approved drug may be a drug approved by the U.S. FDA and/or EMA or other foreign drug regulatory agencies. The compound may be in its free form, salt form or polymorphic form.

Another feature that can be imparted by methods that improve the solubility of drugs/compounds is the ability to increase the storage stability of sugar-compounds.

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

In all the following examples, unless otherwise indicated, the same conditions were used. The water used was deionized water, distilled water. Unless otherwise indicated, 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 and an IKA model C-mag HS7 electromagnetic stirrer. The rotary evaporator used was a Heidolph Basis Hei-VAP value (No. 560-00000-01-1). The reagents used were as follows: Compound Name CAS Number Purity % Source Sildenafil 139755-83-2 95% Combi Blocks Stevioside 57817-89-7 95+% Ambeed Levaudioside A 58543-16-1 98+% Ambeed Dulcoside B N/A 95+% Matrix Scientific Rubusoside 98+% China n-Octyl Glucose 29836-26-8 CCN Industries Ltd. Example 1-Praziquantel and Stevioside

Although praziquantel is not a proposed erectile dysfunction drug, its complex with DTG illustrates the combination and ability to improve the solubility of PSD. Additional examples are provided to reflect the effects of molar ratios and different non-nutritional sugars used to prepare complexes using different solvents.

Generally, the ingredients are deposited in a sealed container with ethanol and vortexed to form a solution. The solution is centrifuged. The ethanol is evaporated and the dried mixture is dissolved in water. The mixture is centrifuged again and the supernatant is filtered through a membrane. The flow-through is dried to form a mixed praziquantel. In one embodiment, the blending method involves dissolving PSD and sugar in ethanol while stirring, and adjusting the pH as necessary to obtain a completely dissolved and clear reaction mixture. The reaction mixture can then be dried to remove the ethanol. No further water washing or filtering is required.

In this example, a dried single-necked RB flask equipped with a magnetic stirring bar was used. Stevioside (200 mg; 0.248 mmol) and praziquantel (20 mg; 0.064 mmol) were weighed and added to the RB flask, followed by 2.0 mL of anhydrous ethanol (spectrophotometric grade, 95%). In this example, the ratio of stevioside:praziquantel was approximately 9:1. The reaction mixture was stirred vigorously at room temperature of 20°C for 30 minutes. The ethanol was removed from the mixture via a rotary evaporator under reduced pressure at a bath temperature of 35°C to give a white solid. The white solid was dried for about one hour to completely remove the ethanol (EtOH) using vacuum drying and a high vacuum pump at room temperature with an Edvards Model # RV8 electromagnetic stirrer, an IKA Model C-MAG HS7 rotary evaporator, and 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 an RB flask. The vacuum strength was about 1 mm Hg.

Light scattering microscopy of drug to rubusoside at a 1:3 ratio revealed no crystal formation for either rubusoside or the uncomplexed form of praziquantel.

The white solid containing stevioside and praziquantel was then dissolved in 2.0 mL of water under stirring at room temperature for 30 minutes to produce a clear solution. Water was removed from the mixture using a rotary evaporator and a high vacuum pump at a bath temperature of 35°C to obtain a white foamy solid. The white foamy solid was dried under high vacuum at room temperature for another hour to completely remove water, as determined by the change in weight loss. Drying was continued until no further weight loss was observed. Solubility of Praziquantel Does not contain stevioside Contains stevioside In the water 0.04 g/ 100 mL Soluble In ethanol (95%) 9.7 g/ 100 mL Soluble After first dissolving in EtOH, the Insoluble Soluble Example 2 - Leucoside A and Praziquantel

In this example, similar to Example 1 above, another sugar, leucoside A, was evaluated for its ability to improve the insolubility of praziquantel. Leucoside A (50 mg) and praziquantel (5.0 mg) were mixed in distilled water at a weight ratio of about 9:1. The reactants in distilled water were not fully dissolved. The same weight ratio of leucoside A and praziquantel were mixed in 95% ethanol (spectrophotometric grade, 95%) in a RB flask at 20°C. The ethanol was removed using a rotary evaporator under reduced pressure at a bath temperature of 35°C as described above. The leucoside A-praziquantel mixture was turbid, and re-precipitation was also observed after one day at 20°C. Solubility of Praziquantel No leucodermoside A Levaudioside A In the water 0.04 g/ 100 mL Insoluble In ethanol (95%) 9.7 g/ 100 mL Insoluble After first dissolving in EtOH, the Insoluble Insoluble Example 3 - Praziquantel and sucrose

In this experiment, the method was applied to praziquantel and sucrose. As shown below, the combination failed to produce a stable complex when evaluated by NMR. The combination of praziquantel and sucrose is poorly soluble in water and insoluble in 95% ethanol. The mixture was stirred vigorously at room temperature of 20°C for 30 minutes. The ethanol was removed by rotary evaporator under reduced pressure at a bath temperature of 35°C to obtain a white solid. The white solid was further dried under high vacuum for one hour to completely remove residual ethanol, as determined by no further weight change.

The resulting white solid was then dissolved in deionized water (2.0 mL) at room temperature. The reaction was stirred at room temperature for 30 minutes using a solid magnetic stir bar. Water was then removed using rotary evaporation at a bath temperature of 35°C under a high vacuum pump to produce a white foamy solid. The white foamy solid was then dried under high vacuum at room temperature for another hour to completely remove the water.

For the experiments, an aqueous solution of sucrose and praziquantel having a weight ratio of 9:1 was diluted with ethanol at a ratio of four parts aqueous solution to one part ethanol (4:1). Adding ethanol to the aqueous solution improved solubility. The method and apparatus used to remove the ethanol are described in Example 2. This method failed to produce a complex when analyzed by NMR. Example 4 - Caloric Sugar Solubility

In this experiment, the solubility of the following sugars was compared: Rubusoside, Dulcoside A, Leucoside B, Dulcoside B, and Leucoside D. Approximately 5.0 mg of each sugar was attempted to be dissolved in 0.6 mL of water and vortexed for 2 minutes at room temperature. No undissolved Rubusoside was observed. Dulcosides A and B and Leucoside D were partially soluble. Leucoside B was insoluble or poorly soluble in water, with no peaks detectable by NMR. It should be noted that this is not a hemihydrate crystal, which has a much lower solubility and solution rate than the free form. The solubility of these sugars in 95% ethanol and water is provided below: sugar Solubility in water Solubility in 95 % EtOH Rubusoside Soluble 10 mg/mL Dulcoside A 2.28 g/L Partially soluble Dulcoside B (also known as Reb C) Partially soluble Slightly soluble sucrose 204 g / 100 g water Insoluble D-Fructose About 4000 g/L at 25℃ Insoluble Sucralose 110 g/L at 20°C 283 g/L at 20°C Stevioside A (Truvia®) Poorly soluble Poorly soluble Stevioside A4 Poorly soluble Poorly soluble Leucodermoside D 100 mg/ml (88.56 mM) Insoluble Stevioside (an example of a diterpene glycoside) 4 g/L 30 mg/ml n-Octyl Glucose Soluble Soluble n-Dodecyl-β-D-maltoside 50 mg/ml Soluble

In another experiment, 50 mg of stevia was dissolved in 2.0 mL of water or 2.0 mL of 95% ethanol. It was observed that stevia was soluble in both water and ethanol.

In another experiment, 50 mg of leucoside A was dissolved in 2.0 mL of water or 2.0 mL of 95% ethanol. It was observed that leucoside A was soluble in water and insoluble or partially soluble in ethanol.

In another experiment, 50 mg of sucralose was dissolved in 2.0 mL of water or 2.0 mL of 95% ethanol. Sucralose was observed to be soluble in water and slowly soluble in ethanol. In this experiment, sucralose took 2 hours to dissolve at room temperature by slow dissolution.

In another experiment, 50 mg of n-dodecyl-β-D-maltoside was dissolved in 2.0 mL of water or 2.0 mL of 95% ethanol. It was observed that n-dodecyl-β-D-maltoside was soluble in both water and ethanol.

In another experiment, 50 mg of n-octylglucose was dissolved in 2.0 mL of water or 2.0 mL of 95% ethanol. It was observed that n-octylglucose was soluble in water and ethanol. Example 5 - Rubusoside and Sildenafil

In a prophetic example, rubusoside (50 mg) and sildenafil (5 mg) (VIAGRA®) in a 9:1 ratio were mixed in 2.0 mL of 95% ethanol to produce a mixture and allowed to dissolve at 20°C. The ethanol in the mixture was then evaporated. The resulting powder was then redissolved in 2.0 mL of water and the NMR of the solid was evaluated to determine whether a complex was formed. NMR indicated that a complex had been formed. In all examples regarding sildenafil, the sildenafil used was obtained from Ambeed Chemicals, Cas number 57817-89-7. Possible hydrogen bonds that can be formed to produce a complex are depicted in Figure 1. It should be noted that sildenafil can be classified as moderately water-soluble. However, improving the water solubility of moderately soluble drugs will be beneficial in terms of the amount of drug that must be administered to an individual, as well as being advantageous if it is to be used to cross the skin barrier in a topical application form. Therefore, improving the water solubility of moderately water soluble ED drugs is also contemplated herein. Example 6 - Sildenafil and Stevioside

While stirring with a magnetic stir bar, sildenafil (5 mg) and stevioside (84.8 mg) in a 1:2 molar ratio were dissolved in 50 mL of 85% ethanol in a RB flask. The pH of the reaction mixture was adjusted to 5.8 with 0.1 N citric acid at 20°C. After dissolution, the ethanol was removed by drying with a rotary evaporator to obtain a white crystalline powder.

A powder containing sildenafil and stevia in complex form was placed in gastric juice with a pH of 8.5 at 20°C and observed for 4 hours (Carolina gastric juice, artificial laboratory grade, obtained from www.carolina.com/specialty-chemicals-d-l/gastric-juice-artificial-laboratory-grade-500-ml/864603.pr, containing 99.18% water, 0.5% pepsin (Cas No. 9001-75-6), 0.22% HCl (Cas No. 7647-01-0), 0.1% viniferin (89-83-8)). No precipitate was observed after 4 hours at pH 8.5 even at 20°C.

Stability at this pH is relevant because this is the pH of the duodenum. Orally administered pellets (e.g., tablets, chewing gum, capsules, and the like) lacking any coating will remain in the stomach for approximately 2-4 hours, then pass into the small intestine and subsequently into the large intestine. No precipitate was observed and the solution remained colorless. The pH of the liquid sample of sildenafil-stevioside was approximately pH 4.8 before it was added to the gastric fluid. The gastric fluid was evaluated and returned to a pH of 8.5 after the addition of the liquid sample of the sildenafil-stevioside complex. Example 7 - Stevioside and Sildenafil

In another test, it was observed that a 2:1 molar ratio of stevioside:sildenafil produced a complex when prepared using the same method as in Example 6. The method of Example 6 was used to evaluate the stability of a 2:1 molar ratio of sugar to drug in a complex under conditions that simulated the duodenum. 1.2 mg of the formed complex was placed in 1.5 mL of gastric fluid and the pH was reduced to 2.0. The complex remained stable for at least 4 hours. Example 8 - Stevioside and Sildenafil

Step 1: In a dried single-necked RB flask equipped with a magnetic stirring bar and a septum (flask cap), 5 mg of sildenafil (0.01054 mmol) and 16.95 mg of stevioside (1:2 molar ratio) were weighed and charged into the RB flask and dissolved in 85% ethanol (about 2.0 mL, denatured 85% ethanol) at ambient temperature. The reaction mixture was vigorously stirred at room temperature for 30 minutes. The resulting solution was slightly turbid or had visible solid particles. 0.1 N citric acid was added to the solution, making the solution homogeneous and clear; the addition of citric acid lowered the pH from 6.1 to 5.5. The ethanol was then removed under reduced pressure via a rotary evaporator at a bath temperature of 35° C. to obtain a white solid. The white solid was dried under high vacuum for one hour to completely remove the ethanol (no further weight loss was observed).

Step 2: The resulting white solid was then dissolved in 2.0 mL of water in a RB flask with a magnetic stir bar at room temperature. The reaction mixture was stirred at ambient temperature for 30 minutes. Water was removed using a rotary evaporator and a high vacuum pump at a bath temperature of 35°C, thereby obtaining a white foamy solid. The white foamy solid was then dried under high vacuum for one hour at room temperature to completely remove the water. The weight of the flask was checked while drying until no further weight loss was observed. The peaks shown by NMR indicated that sildenafil was 100% dissolved in water.

In another experiment, a 1:10 molar ratio of sildenafil:stevioside (5 mg:84.8 mg) was dissolved using the same procedure as in step 1 above. Both compounds dissolved slowly; after 30 minutes, the compounds appeared to be dissolved, but the solution appeared slightly cloudy. The ethanol was then dried to obtain a solid.

The Sildenafil: Stevioside solid was then dissolved in 2 mL of water as described above in Step 2 and appeared to dissolve immediately. However, after a few minutes, a white cloudy precipitate began to form. The white cloudy solution became even whiter after 30 minutes. After concentration, 89.8 mg of the solid was dissolved in 2.0 mL of D ₂ O and analyzed by NMR. The solution was again white and cloudy and did not dissolve quickly. NMR indicated that Sildenafil did not form a complex with Stevioside when a 1:10 ratio was used. Example 9 - 1:10 Molar Ratio of Sildenafil to Stevioside

A 1.0:10.0 molar ratio of sildenafil:stevioside (5 mg:84.8 mg) obtained at the end of step 2 by the method described in Example 8 was then dissolved in 2.0 mL of distilled water. The reaction mixture was determined to have a pH of 6.4 and was white and turbid. 50 μL of 0.1 N HCl was added to the turbid white solution, and the solution became less turbid and had a pH of about 5.8. When another 50 μL of 0.1 N HCl (100 μL total) was added to the solution, the pH became about 5.2 and the turbidity was reduced but still turbid. When another 50 μL of 0.1 N HCl (i.e., 150 μL total) was added to the solution, the solution became clear and homogeneous and had a pH of about 4.8. The clear solution was then dried as described in step 2 of Example 8. 10 mg of the dried solid was then dissolved in 0.6 mL D ₂ O. NMR revealed that a 1:10 ratio of sildenafil and stevioside produced a drug-sugar complex with the addition of acid, and the complex was 100% soluble in water using this method. In addition, no precipitate formation was observed when the sample in D ₂ O was kept at room temperature for 3 days. Example 10 - Sildenafil and Stevioside

In another experiment, it was evaluated whether sildenafil and stevioside in a 1:10 weight ratio could form a complex using an electrolyzer instead of acid. Sildenafil (5 mg; 0.01054 mmol) and stevioside (50 mg, 0.0778 mmol) were treated as follows.

Step 1: In a fresh 20 mL clear RB flask, dissolve 5 mg sildenafil and 50 mg stevioside in 2.0 mL 85% ethanol at ambient temperature. Stir the reaction mixture for 15 minutes and produce a turbid solution.

An electrolyzer using electrodes (anode and cathode) is set up, and the platinum and copper metal plates of the electrodes are immersed in the reaction mixture. The reaction mixture is vigorously stirred at room temperature for 30 minutes while sending low to high energy, that is, a voltage of 3 vDC to 24 vDC is applied starting over 30 minutes. The reaction mixture is still turbid or there are visible solid particles. Ethanol is removed from the reaction mixture using a rotary evaporator under reduced pressure at a bath temperature of 35°C to obtain the white solid described above. The white solid is dried under high vacuum for one hour to completely remove the ethanol, and is confirmed by the absence of further weight loss.

Step 2: A magnetic stir bar was added to the flask with the dry white solid and 2.0 mL of distilled water was added at room temperature to dissolve the solid. The reaction mixture was stirred at ambient temperature for 20 minutes. The solution became white and cloudy. The above electrolysis method was applied for 30 minutes and the solution was observed to become light orange due to the metal. The water was removed using a rotary evaporator under a high vacuum pump at a bath temperature of 35°C, thereby obtaining a white foamy solid. The white foamy solid was further dried under high vacuum for another hour at room temperature to completely remove the water. The weight of the sample was analyzed while drying until no further weight loss was observed, indicating that all water had been removed.

Then 7 mg of the sample was dissolved in 6.0 mL of D ₂ O for NMR analysis. NMR indicated that sildenafil did not form a complex with stevioside under these conditions. Example 11-1 : 5 molar ratio of sildenafil to stevioside

In this example, a 1:5 molar ratio of sildenafil to stevioside was tested with the addition of hydrochloric acid (HCl) to determine whether a water-soluble complex could be formed using the acid at this ratio. Step 1: 5 mg of sildenafil and 42.41 mg of stevioside were dissolved in 2.0 mL of 95% ethanol. Again, the compound was observed to dissolve slowly after 3 minutes, forming a slightly turbid solution; the resulting solution had a pH of approximately 5.2.

To the turbid solution was added 50 μL of 0.1 N HCl, which made the solution clear and homogeneous; the pH of the acidic solution was about 4.9. The reaction mixture was then dried as described in Example 8 to yield a solid.

The dried solid was then dissolved in 2.0 mL of distilled water; it was noted that the solid dissolved immediately and a clear homogeneous solution was produced. When an additional 50 μL of 0.1 N HCl was added to the solution, no change was seen in the reaction mixture.

For NMR, 10 mg of the obtained solid sample was dissolved in 0.6 mL D ₂ O. The dissolved 10 mg sample again produced a clear and homogeneous solution. 1H-NMR showed drug peaks in equimolar ratio (1:5), indicating that the sildenafil-stevioside complex has 100% solubility in water and a complex is formed between the drug and sugar. The complex in D ₂ O remained stable for 9 days without any observable precipitate formation. Example 12 - Complex of Sildenafil, Rubusoside and Stevioside

In this example, sildenafil was combined with two sugars (rubusoside and stevioside) and then analyzed. The following sildenafil:rubusoside:stevioside ratio was used: 1.0:7.38:1.0 molar ratio; 5 mg:50.0 mg:8.4 mg.

Step 1: Weigh the three materials and place in a RB flask and dissolve in 2.0 mL 95% ethanol. The reagents were observed to dissolve slowly and produce a reaction mixture with a pH of about 6.1. Dry the reaction mixture as described previously.

Step 2: The dried reaction mixture was then dissolved in 2.0 mL of distilled water (pH about 6.1), where solids were observed to dissolve immediately. However, precipitate formation was observed after the solution was allowed to stand for 30 minutes. 1 drop of 1 N HCl was added to the precipitated reaction mixture, whereupon the reaction mixture became clear and homogeneous. It should be noted that in some cases, acid, base or buffer may be added during step 1 or in step 2. The pH of the resulting reaction mixture was about 2.0. The reaction mixture was then dried as described in Example 7.

The dried solid obtained after adding one drop of HCl was analyzed by NMR, where 10 mg of the dried sample was dissolved in 0.6 mL of D ₂ O, resulting in a clear homogeneous solution. 1H-NMR analysis showed that the drug peaks were equimolar ratios of sildenafil and rubusoside and stevioside, indicating that the sildenafil-stevioside complex has 100% solubility in water. The solution dissolved in D ₂ O remained clear and homogeneous for 3 days without forming a precipitate.

The relevance of this example is that it can be combined with different steviol sugars to form complexes, as long as an acid solubilizing agent is used. Example 13 - 1 : 5 molar ratio of sildenafil to stevioside in the presence of citric acid

In this experiment, the ability of citric acid to improve the formation of sildenafil and stevioside complexes at a 1:5 molar ratio of sildenafil to stevioside was analyzed. As described above, 5 mg of sildenafil and 42.41 mg of stevioside were dissolved in 95% ethanol at ambient temperature with stirring. The reaction mixture slowly dissolved after 3 minutes, producing a slightly turbid solution with a pH of 5.2. When 50 μL of 0.1 N citric acid was added to the solution, the solution became clear and homogeneous with a pH of 5.8. The reaction mixture was dried as described in Example 7. The dried solid was dissolved in 2.0 mL of distilled water and was observed to dissolve immediately and produce a clear homogeneous mixture.

The dissolved mixture was dried again as described in Example 7. 10 mg of the dried solid sample was dissolved in 0.6 mL of D ₂ O to produce a clear homogeneous reaction mixture. When analyzed by 1H-NMR, a drug peak was observed, which indicated the formation of a complex and indicated that the complex had 100% solubility in water, indicating that citric acid could also aid in complex formation. The reaction mixture was stable for 3 days and no visible precipitate was formed. Example 14 - 1 : 3 molar ratio of sildenafil to stevioside in the presence of citric acid

In this experiment, a 1:3 molar ratio of sildenafil to stevioside was prepared and adjusted with citric acid to see if complete solubility could be achieved. 5.0 mg of sildenafil and 25.44 mg of stevioside were dissolved in 2.0 mL of 95% ethanol, resulting in a solution that appeared slightly turbid and had a pH of approximately 5.2. When 50 µL of 0.1 N citric acid was added to the reaction mixture, the solution became clear and homogeneous with a pH of approximately 4.9. The reaction mixture was then dried as described above.

The dried solid obtained from the citric acid treated reaction mixture was then dissolved in water to produce a reaction mixture with a pH of 5.5. The solid was observed to dissolve immediately in the distilled water and produce a clear homogeneous solution. To this solution was added 50 μL of 0.1 N citric acid. The solution with the added citric acid remained clear and had a pH of approximately 4.6. The reaction mixture at pH 4.6 was dried as previously described until all water was removed.

10 mg of the dried reaction mixture was dissolved in 0.6 mL D ₂ O to produce a homogeneous and clear solution. 1H-NMR gave a drug peak at an equimolar ratio of 1:3, indicating 100% solubility of sildenafil in the complex in aqueous solution. The 1:3 molar ratio of the complex dissolved in D ₂ O was kept in solution for 3 days. Example 15 - 1 : 2 molar ratio of sildenafil to stevioside in the presence of citric acid

In this experiment, the dissolution of sildenafil and stevioside in a 1:2 molar ratio was analyzed by dissolution with citric acid. For the experiment, 5.0 mg of sildenafil and 16.95 mg of stevioside were dissolved in 50 mL of distilled water. The resulting reaction mixture dissolved after 3 minutes of stirring, but was still cloudy and had a pH of 6.1. To this reaction mixture was added 100 µL of 0.1 N citric acid and the resulting reaction mixture became clear and homogeneous (i.e., no longer cloudy). The pH of the homogeneous mixture was 5.5. The mixture was dried as described above to obtain a white solid.

When the reaction mixture was redissolved in 2.0 mL of distilled water, the solid dissolved immediately, yielding a homogeneous and clear solution. The solid was then dried again as described above.

10.0 mg of the resulting white solid was dissolved in 0.6 mL of D ₂ O, which immediately turned into a clear solution. The solution was analyzed by 1H-NMR, confirming the presence of a 1:2 equimolar ratio of sildenafil-stevioside complex and indicating that the sildenafil complex had 100% solubility in water. Example 16 - 1 : 2 molar ratio of praziquantel to stevioside in the presence of HCl

In this example, a 1:2 molar ratio of praziquantel to stevioside was analyzed with the addition of HCl. For example, 5 mg of praziquantel and 20.57 mg of stevioside were mixed in 2.0 mL of 95% ethanol. Dissolution of the compounds proceeded slowly, with both compounds appearing to dissolve after 3 minutes. The resulting solution had a pH of approximately 5.2 and was slightly turbid. 25 µL of 0.1 N HCl was added to the solution, and the turbidity disappeared completely. The reaction mixture was then dried as described above to produce a white solid.

The resulting white solid was then dissolved with 2.0 mL of distilled water, yielding a mixture with a pH of approximately 4.7. Dissolution occurred immediately and resulted in a clear solution; however, after 15 minutes, the solution became white and turbid.

When 10 mg of the white solid obtained above was dissolved in 0.6 mL D ₂ O, a white turbid solution was again produced. NMR of the solution indicated that at a 1:2 molar ratio, praziquantel was only partially soluble in water. Therefore, as shown in this example, the molar ratio of rubusoside to the insoluble drug praziquantel also correlates with solubility. As indicated by these results, the dissolution of the drug is not linear. Example 17 - Evaluation of in vitro treatment of Schistosoma mansoni

This experiment is provided to show that the water-soluble complex comprising praziquantel and rubusoside remains effective in killing schistosomes, demonstrating that the complex is soluble and maintains parasiticidal activity.

Schistosoma mansoni is a waterborne parasite that affects humans. It is a member of the schistosome (i.e., blood fluke) family. Other types of schistosomes that cause schistosomiasis include S. mekongi , S. intercalatum , S. japonicum , and S. guineensis (previously considered synonymous with S. intercalatum). These organisms can also parasitize birds and mammals. When humans are infected, the adult parasites reside in blood vessels near the human intestines, causing intestinal schistosomiasis, in which clinical symptoms are caused by egg laying.

In this experiment, approximately 130 newly transformed schistosomula (NTS) cutaneous stage schistosomes of S. mansoni were cultured in M199 medium at 37°C in a 5% _CO2 incubator 1 day after transformation from infective cercariae. After overnight incubation, NTS were exposed to different concentrations of praziquantel alone or a complex of praziquantel and rubusoside for 24 and 72 hours. Parasite images were acquired using a Keyence BZ-X800 microscope, and rubusoside and praziquantel activities were evaluated phenotypically. Both the uncomplexed form of praziquantel and the praziquantel-rubusoside complex had similar parasiticidal activities. The table below indicates the number of viable worms remaining after administration of sugar-free praziquantel or rubusoside-praziquantel complex. Compound 24 -hour exposure LD ₅₀ (µM) 72 -hour exposure LD ₅₀ (µM) Rubusoside-Praziquantel Complex 25.9±0.91 15.9±0.25 Praziquantel only 33.5±5.71 24.3±0.67

NTS survival was assessed by parasite scoring based on the outlined guidelines indicated below. In addition, NTS survival was assessed by measuring parasite ATP levels using Promega's CellTiter-Glo® Luminescence Cell Viability Assay according to the manufacturer's instructions. The experiment was repeated three times. The effects of rubusoside and praziquantel (PZQ) were determined using the equation % effect = 100-(mean (test) x 100/mean (control)). The _LD50 was then calculated from this.

After 72 hours of exposure, praziquantel alone had an _LD50 of 33.9±0.64 µM for the organism. The rubusoside-praziquantel formulation produced an _LD50 of 18.3±0.94 µM. The difference in the effects of praziquantel alone and praziquantel-rubusoside on parasite survival was not statistically significant. Scoring criteria : 3=Motile, no change in morphology or transparency of the trematodes 2=Decreased motility and/or some damage to the integument noted, as well as decreased transparency and particle size 1=Substantially decreased motility and/or severe damage to the integument observed, as well as high opacity and high particle size 0=Death 18-Dulcoside A and Praziquantel

In this experiment, dulcoside A (28 mg) and praziquantel (4.5 mg) were used in a weight ratio of 84:16 (or 5.25:1). Both dulcoside A and praziquantel were insoluble in 95% ethanol and in a water bath at 20°C. It was determined that the described method did not allow dulcoside A to form a hydrogen bond with praziquantel to increase the solubility of praziquantel. This example shows that although another specified sugar can make the drug soluble in 95% ethanol, not all steviosides can do so. Example 19 - Leucoside B and Praziquantel

In this experiment, a 9:1 weight ratio of ledioside B (28 mg) to praziquantel (3 mg) was used. Both ledioside B and praziquantel were insoluble in 95% ethanol and in a water bath at 20°C. It was determined that the described method did not allow leadioside B to form a hydrogen bond with praziquantel to increase the solubility of praziquantel. This example shows that although other steviosides can solubilize drugs, not all steviosides can do so. Example 20 - Dulcoside B and Praziquantel

In this experiment, dulcoside B (50 mg) and praziquantel (5.0 mg) were used in a 9:1 weight ratio in 2.0 mL of 95% ethanol at 20°C. As in the rubusoside-praziquantel experiment, the material was observed to dissolve slowly in the ethanol. After approximately 10 minutes, the reaction mixture became a clear and colorless solution. The ethanol was removed as described in the other examples and 2.0 mL of water was added to the sample. Again, the powder was redissolved in water to become a clear and colorless solution. NMR confirmed that a complex was formed between dulcoside B and praziquantel, and when present, the complex was fully soluble in water. Example 21 - Leucoside D and Praziquantel

In step 1, a 9:1 weight ratio of leucoside D (50 mg) and praziquantel (5.0 mg) was used. Both leucoside D and praziquantel were insoluble in 95% ethanol and in water at 20°C. The inability of leucoside D to form hydrogen bonds (and thus complexes) with praziquantel was determined using the described method. The combination was insoluble and no complex was formed as determined by NMR. This example shows that not all steviosides can dissolve drugs, but another of the listed sugars can. Example 22 — D - Glucose or D - Fructose and Praziquantel

In this experiment, D-glucose and praziquantel were mixed in a 9:1 weight ratio. At 20°C, 200 mg of D-glucose and 20 mg of praziquantel were insoluble in 95% ethanol and water. D-glucose was soluble in water, but praziquantel was observed to adhere to the flask walls. From this experiment, it was determined that the use of D-glucose did not make praziquantel more soluble and that praziquantel did not form a complex with D-glucose, as confirmed by NMR.

The same experiment was performed using D-fructose instead of D-glucose. In this experiment, 200 mg of D-fructose and 20 mg of praziquantel were stirred in a 9:1 weight ratio at 20°C in the presence of 95% ethanol. Fructose is insoluble in 95% ethanol but soluble in water. D-fructose and praziquantel do not form a complex and do not make praziquantel soluble or more soluble in water as determined by NMR. Example 23 - Rubusoside and Prasin

In this example, 50 mg of rubusoside and 5 mg of prednisone were mixed in 2.0 mL of 95% ethanol at 20°C, which was also a 9:1 weight ratio of sugar (rubusoside) to drug (prednisone) and stirred as described above. The reaction mixture slowly dissolved. After 5 minutes at 20°C, the reaction mixture became a clear colorless solution. The ethanol was removed from the mixture using a rotary evaporator and a high vacuum pump at a bath temperature of 35°C. The dry powder was then redissolved in 2 mL of deionized water to produce a homogeneous white turbid mixture with a syrupy consistency.

Using NMR, it was determined that the method did not produce a water-soluble rubusoside-presin complex. NMR showed only trace amounts of NMR peaks.

In another example, testosterone cypionate and stevioside were tested at a 3:1 sugar to drug ratio using 23.4 mg stevioside and 5 mg stevioside. Both slowly dissolved in 85% (denatured) ethanol to give clear and colorless solutions. However, after the mixture was dried and then dissolved in water, only a white turbid solution was formed. NMR indicated that no complex was formed. Testosterone cypionate was also tested with sugar at a 1:10 molar ratio. Testosterone cypionate and stevioside were dissolved in 85% ethanol as before. However, after drying, a white turbid solution was produced again when the powder was dissolved in 2 mL of water. Citric acid (0.1 N) was added to the solution, but no change in the white turbid solution was seen. NMR showed that no complex was formed by adding citric acid. Weight ratio, but it also failed to form a complex with rubusoside (data not shown). The same ratio was also tested using 0.2 M sodium carbonate and carbonate buffer at pH 9.4. When evaluated by NMR, no complex was formed using alkaline buffer. The same 1:10 molar ratio experiment was also performed using 0.1 N aqueous sodium hydroxide solution to see if the white turbid solution would change. NMR also showed no complex formation. Example 24 - Penicillin V and Rubusoside

Rubusoside (50 mg) and penicillin V (phenoxymethyl penicillin) (5.0 mg) were dissolved in 95% ethanol (2.0 mL) at 20°C in a weight ratio of 9:1. Ethanol was removed from the mixture by rotary evaporator under reduced pressure at a bath temperature of 35°C to obtain a powder. The solid was then dissolved in water, revealing the formation of a complex between rubusoside and penicillin V. Solubility of Penicillin V Hydrochloride (350.4 MW) No rubusoside Rubusoside In the water 0.636 mg/mL, or 24 mg/100 mL at pH 1.8 when acidified with HCl Soluble In ethanol Soluble Soluble After first dissolving in EtOH, the N/A Soluble Example 25 - Acycloguanosine and Rubusoside

Acycloguanosine has a solubility of less than 1 mg/ml, which generally means that it is slightly soluble or insoluble. In this experiment, rubusoside (50 mg) and acycloguanosine (5 mg) in a weight ratio of 9:1 were dissolved in 2.0 mL of 95% ethanol at 20°C. The ethanol was removed from the mixture via a rotary evaporator under reduced pressure at a bath temperature of 35°C to obtain a powder. The solid was then dissolved in water, showing that a complex was formed between rubusoside and acycloguanosine. Solubility of Penicillin V Hydrochloride (350.4 MW) No rubusoside Rubusoside In the water 24 mg/100 mL at pH 1.8 or less than 1 mg/mL at 55°C Soluble In 95% ethanol Soluble Soluble After first dissolving in EtOH, the N/A Soluble Example 26 - Rubusoside and Ibuprofen

In a prophetic example, rubusoside (50 mg) and ibuprofen (5.0 mg) in a 9:1 ratio were mixed (stirred) in 2.0 mL of 95% ethanol to produce a mixture and allowed to dissolve at 20°C. The ethanol in the mixture was then evaporated. The resulting powder was then redissolved in 2.0 mL of water, and the NMR of the solid was evaluated for the presence of a new hydrogen bond connecting the ibuprofen and rubusoside. Example 27 - Rubusoside and Aceclofenac

In a prophetic example, rubusoside (50 mg) and aceclofenac (5.0 mg) in a 9:1 ratio were mixed in 2.0 mL of 95% ethanol and allowed to dissolve at 20°C to produce a mixture; the ethanol was then removed as described. The resulting powder was then redissolved in 2.0 mL of water, and the NMR of the solid was evaluated for the presence of a new hydrogen bond connecting rubusoside and aceclofenac.

Aceclofenac is a nonsteroidal anti-inflammatory drug. Diclofenac is its analog. It is reasonable to assume that diclofenac will also dissolve in the same manner as aceclofenac. Diclofenac is a metabolite of aceclofenac, which are 4'-hydroxyaceclofenac (major metabolite), 5-hydroxyaceclofenac, 4'-OH-aceclofenac, and 5-OH-aceclofenac. Aceclofenac salts include salts with cytosine, piperidine, L-lysine, and γ-aminobutyric acid, and are also encompassed in terms of dissolution using the methods disclosed herein. Experiment 28 - Rubusoside and Paclitaxel

At 20°C, rubusoside and paclitaxel in a weight ratio of 9:1 (50 mg to 5 mg) were slowly dissolved in 95% ethanol to produce a homogeneous clear colorless solution after 10 minutes. When the same amount of paclitaxel was dissolved in the same volume of water, a white turbid liquid was obtained, which remained so even after 30 minutes. It was determined that this method could not produce a hydrogen-bonded complex soluble in water.

Ethanol was removed from the mixture via a rotary evaporator under reduced pressure at a bath temperature of 35°C to give a white solid. The dried solid was then dissolved in water. The solution was observed to be white and turbid after 30 minutes, and no colorless or clear solution was obtained, indicating that complexation between rubusoside and paclitaxel occurred. Solubility of paclitaxel No rubusoside Rubusoside In the water 0.1 µg/ml Insoluble In ethanol 1.5 mg/ml Soluble After first dissolving in EtOH, the N/A Insoluble

The white solid containing rubusoside and paclitaxel was then dissolved in 2.0 mL of water under stirring at room temperature for 30 minutes to produce a clear solution. Water was removed from the mixture using a rotary evaporator and a high vacuum pump at a bath temperature of 35°C to obtain a white foamy solid. The white foamy solid was then dried under high vacuum at room temperature for one hour to completely remove water, as determined by the change in weight loss. Drying was continued until no further weight loss was observed.

More than ten intermolecular hydrogen bonds (e.g., OH--O; OH--N; and NH--O) are obtained between rubusoside and paclitaxel. The molecular weight (MW) of paclitaxel is 853.92, and the elemental analysis shows C, 66.11; H, 6.02; N, 1.64; and O, 26.23. Example 29 - Praziquantel and sucrose

In this experiment, the method was applied to praziquantel and sucrose. The combination of praziquantel and sucrose is poorly soluble in water and insoluble in 95% ethanol. The mixture was stirred vigorously at room temperature of 20°C for 30 minutes. The ethanol was removed by rotary evaporator under reduced pressure at a bath temperature of 35°C to obtain a white solid. The white solid was further dried under high vacuum for one hour to completely remove residual ethanol, as determined by no further weight change.

The resulting white solid was then dissolved in deionized water (2.0 mL) at room temperature. The reaction was stirred at room temperature for 30 minutes using a solid magnetic stir bar. Water was then removed using rotary evaporation at a bath temperature of 35°C under a high vacuum pump to produce a white foamy solid. The white foamy solid was then dried under high vacuum for another hour at room temperature to completely remove water.

For the experiments, an aqueous solution of sucrose and praziquantel having a weight ratio of 9:1 was diluted with ethanol at 4 parts aqueous solution to 1 part ethanol (4:1). Adding ethanol to the aqueous solution improved solubility. The method and apparatus for removing ethanol are described in Example 2. The experiments failed to produce a complex between praziquantel and sucrose. Solubility of Praziquantel No sucrose With sucrose In the water 0.04 g/ 100 mL Insoluble In ethanol (95%) 9.7 g/ 100 mL Insoluble After first dissolving in EtOH, the Insoluble Insoluble Example 30 - Gradually increasing the ratio of rubusoside to praziquantel

In this experiment, the optimal molar ratio of rubusoside to praziquantel was evaluated.

Step 1: In an oven-dried single-necked RB flask equipped with a magnetic stir bar and a septum (for sealing the flask), place Rubusoside (10.0 mg; 15.56 mmol) and Praziquantel (5.0 mg; 16.00 mmol) in a 2:1 ratio. Add ethanol (1 mL) to the RB flask. Stir the reaction mixture vigorously at room temperature for 30 minutes. This produces a clear solution. Remove ethanol via a rotary evaporator under reduced pressure at a bath temperature of 35°C to obtain a white solid. The white solid is then dried using high vacuum for one hour to completely remove the residual ethanol.

Step 2: The white solid obtained from step 1 was then dissolved in 1.0 mL of deionized water in a RB flask at room temperature using a magnetic stir bar. The reaction mixture was stirred at ambient temperature (room temperature) for 30 minutes. A turbid solution with some particles was observed. Using a high vacuum pump, water was removed using a rotary evaporator, wherein the RB flask was kept at a bath temperature of 35°C, and a white foamy solid was produced upon drying. The white foamy solid was further dried under high vacuum for one hour at room temperature to completely remove the water. The weight was checked while drying until no further weight loss was found. The molar ratio of rubusoside to praziquantel from this experiment was 0.01556 to 0.016, i.e., 0.972:1.00 (close to 1:1). Both materials were observed to be soluble in ethanol to produce clear colorless solutions. When the materials were dissolved in water, the solid was observed to dissolve slowly, and the final solution was cloudy and still had particles present. 1H-NMR analysis showed that the drug solubility increased from 1.5 to 1.73, which also indicated complex formation. Material Molecular weight weight Millimole (mmol) Equivalent Rubusoside 642.74 10 mg 0.01556 0.972 Praziquantel 312.41 5 mg 0.016 1.00

The same experiment was performed with a 1:1 ratio of rubusoside to praziquantel. In an oven-dried single-necked RB flask equipped with a magnetic stir bar and septa, rubusoside (10.0 mg) and praziquantel (10.0 mg) were placed in a 1:1 ratio. Ethanol (95%) (1 mL) was added to the RB flask. The reaction mixture was stirred vigorously for 30 minutes at room temperature. The ethanol was removed by a rotary evaporator under reduced pressure in a 35°C water bath. A white solid was obtained, and then it was further dried under high vacuum for one hour to completely remove the residual ethanol. A magnetic stir bar was added to the obtained white solid and the solid was dissolved in deionized water (1.0 mL) at room temperature. The reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was insoluble and turned into a white solid. Stirring was continued for another 2 hours, but no solubility change was observed for the 1:1 ratio of the compound. Using a rotary evaporator and a high vacuum pump again, the water in the RB flask was removed in a 35°C water bath to produce a white foamy solid. The white foamy solid was then dried under high vacuum for one hour at room temperature to completely remove the water. The weight was checked while drying, and the white compound was dried until no further weight loss was found. As can be seen in the table below, the molar ratio of rubusoside to praziquantel is 0.01556:0.032, or 0.45:1.00 (approximately 1:2). Both materials are soluble in ethanol and not very soluble in water. Material Molecular weight weight Millimole (mmol) Equivalent Rubusoside 642.74 10 mg 0.01556 0.45 Praziquantel 312.41 10 mg 0.032 1.00

1H-NMR analysis determined that a 1:1 ratio of rubusoside and praziquantel was ineffective in the formation of a complex between rubusoside and praziquantel. The solubility was found to decrease from 1.5 to 0.89.

The same experiment was performed with a 3:1 ratio of rubusoside to praziquantel. Despite the increased solubility, this ratio was determined to be less soluble than the 2:1 ratio of rubusoside to praziquantel. Using the same procedure described for the 1:1 and 2:1 ratio examples, 7.5 mg of rubusoside and 2.5 mg of praziquantel were dissolved in 1 ml of 95% ethanol to produce a clear, colorless solution. When the same ratio was dissolved in deionized water after the ethanol dissolution step, solids were initially present but slowly dissolved, producing a slightly turbid solution with no discernible particles. The 3:1 ratio reduced the solubility of praziquantel from 1.5 to 0.65 as determined by 1H-NMR analysis. The molar ratio of rubusoside to praziquantel was 0.07001 to 0.04801, which is a 1.48:1 or approximately 3:2 ratio. A 1:1 ratio works but is not as effective. Material Molecular weight weight Millimole Equivalent Rubusoside 642.74 45 mg 0.07001 1.46 Praziquantel 312.41 15 mg 0.04801 1.00

In another example, rubusoside and praziquantel were analyzed at a 4:1 weight ratio (50 mg and 12.5 mg, respectively). The compounds were dissolved and processed as described above for other examples. The compounds dissolved in ethanol produced a clear solution, while the particles dissolved in water produced a turbid solution, but the particles were not visually distinguishable. The molar ratio of rubusoside to praziquantel was 0.07780 to 0.04001, i.e., 1.94:1 or about 2:1. Material Molecular weight weight Millimole Equivalent Rubusoside 642.74 50 mg 0.0778 1.94 Praziquantel 312.41 12.50 mg 0.04001 1.00

Rubusoside and praziquantel were then evaluated in a 5:1 ratio (50 mg:10 mg) following the same procedure. In ethanol, both materials dissolved readily, yielding clear and colorless solutions. When the compounds were dissolved in water, the solids dissolved slowly, yielding a slightly turbid solution with visible particles. The molar ratio of rubusoside to praziquantel was 0.0778 to 0.03201, or 2.43:1. Material Molecular weight weight Millimole Equivalent Rubusoside 642.74 50 mg 0.0778 2.43 Praziquantel 312.41 10 mg 0.03201 1.00

Rubusoside and praziquantel were then evaluated at a 6:1 weight/weight ratio (60 mg and 10 mg) using the same method described above. Both compounds were soluble in ethanol, yielding clear and colorless solutions. When the compounds were dissolved in water, solids were initially present, which completely dissolved over time, yielding a slightly turbid solution, and no particles were present. The molar ratio of rubusoside to praziquantel was 0.09335 to 0.03201, or 2.92:1. Material Molecular weight weight Millimole Equivalent Rubusoside 642.74 60 mg 0.09335 2.92 Praziquantel 312.41 10 mg 0.03201 1.00

Rubusoside and praziquantel were then evaluated at a 7:1 weight/weight ratio (70 mg and 10 mg, respectively) using the same method described above. Both compounds were soluble in ethanol, yielding clear and colorless solutions. When the compounds were dissolved in water, they were readily soluble and no particles were observed. Material Molecular weight weight Millimole Equivalent Rubusoside 642.74 70 mg 0.109 3.40 Praziquantel 312.41 10 mg 0.03201 1.00

The molar ratio of rubusoside to praziquantel is 0.109 to 0.03201, or 3.40:1. Therefore, a molar ratio of rubusoside to praziquantel of 3:1 can also play a dissolving role.

Rubusoside and praziquantel were then evaluated at a 9:1 weight/weight ratio (50 mg and 5 mg, respectively) using the same method described above. Both compounds were soluble in ethanol, yielding clear and colorless solutions. The compounds were readily soluble in deionized distilled water, and no particles were observed, and a clear, colorless, homogeneous solution was produced. The molar ratio of rubusoside to praziquantel was 0.078 to 0.016, which is also a 4.86:1 ratio. Material Molecular weight weight Millimole Equivalent Rubusoside 642.74 50 mg 0.078 4.86 Praziquantel 312.41 5 mg 0.016 1.00 Example 31 - Tadalafil : Stevioside

Tadalafil is soluble in chloroform and is considered insoluble in water. In this example, the following steps were performed. Step 1: In an oven-dried single-necked RB flask equipped with a magnetic stir bar and septum, tadalafil and stevioside were added in a 1:3 molar ratio as indicated below. Approximately 2.0 mL of 85% ethanol was added at ambient temperature. It should be noted that no difference was observed in the results when 95% ethanol was used, so for the examples, 85% ethanol was used. Material Molecular weight weight Millimole Equivalent Tadalafil T-80 389.4 5 MG 0.01248 1.00 Stevioside 804.87 31 MG 0.03852 3.00 Denatured ethanol: 2 mL Deionized water: 2 mL

When ethanol was added, the solution became cloudy due to the presence of solids; the pH of the solution was about 5.5. The reaction mixture was stirred vigorously at room temperature for 30 minutes. Most reactions had very slight turbidity or the presence of visible solid particles. 150 μL of 0.1 N citric acid was added and the solution became clear and homogeneous with a pH of about 5.2. The ethanol was removed using a rotary evaporator under reduced pressure at a bath temperature of 35°C. The white solid was dried under high vacuum for 1 to 2 hours to completely remove the ethanol, as determined by no further weight loss.

Step 2: Add a magnetic stir bar to the above mixture and dissolve it in water (about 2.0 mL) at room temperature to produce a white turbid solution with a pH of about 3.0. To this solution, add 50 μL of 0.1 N citric acid. NMR was performed as described in the above example and indicated that no complex was formed.

The same experiment was repeated with a 1:3 molar ratio, except that this time no citric acid was added during step 1 (the pH of the solution was about 5.5). The 85% ethanol-tadalafil-stevioside solution became cloudy again with solids present. The solution was dried to remove the ethanol until no further drying was observed as previously described.

The dry powder was then dissolved in 2.0 mL of water and a white turbid solution with a pH of 6.1 was formed, to which 200 μL of 0.1 N HCl was added in 100 μL increments, the pH dropped to 2.5 after the addition of 200 μL. The solution remained turbid. A complex was formed, but it was not 100% soluble. The experiment showed an improvement in solubility in water with the addition of acid (about 2.3% improvement in water solubility). The same experiment was performed using a 1:10 molar ratio and also using buffer. Material Molecular weight weight Millimole Equivalent Tadalafil 389.4 5 MG 0.01248 1.00 Stevioside 804.87 103.3 MG 0.03852 10.00 Denatured ethanol: 2 mL Deionized water: 2 mL

Prior to the addition of buffer, the ethanol solution was cloudy and particles were present; the pH of the solution was approximately 5.5. 200 μL of 9.4 pH 0.1 M sodium carbonate and carbonate solution was added, raising the pH of the total solution to approximately 6.4. The solution remained cloudy and solid particles were visible. The solution was dried as before, and 2.0 mL of water was then added to dissolve the solids. The aqueous solution was white and cloudy, and had a pH of approximately 9.5. NMR was performed as described above, showing no signs of complex formation between stevioside and tadalafil at this molar ratio with the addition of buffer.

Another experiment was performed using a 1:10 molar equivalent of tadalafil to stevioside as follows. Material Molecular weight weight Millimole Equivalent Tadalafil 389.4 5 MG 0.01248 1.00 Stevioside 804.87 103.3 MG 0.03852 10.00 Denatured ethanol: 2 mL Deionized water: 2 mL

Stevioside and tadalafil were in a 1:10 molar ratio, 85% ethanol was added, and the solution was stirred for about 30 minutes. The solid slowly became soluble and a clear homogeneous solution with a pH of about 5.0 was produced. No solids appeared. The solution was dried as described previously.

The dry powder was dissolved in 2 mL of water and a white turbid solution with a pH of about 6.0 was formed. 120 μL of carbonate and bicarbonate buffer (pH 9.4) was added to raise the pH to about 7.2. No discernible change was observed in the appearance of the liquid, and no improvement in solubility was observed by NMR.

NMR analysis of the dry powder dissolved in _D2O indicated that the compound did not form a complex at a 1:10 ratio.

In another experiment, a 1:5 ratio of tadalafil to Tween 80 was tried as follows. Material Molecular weight weight Millimole Equivalent Tadalafil 389.4 10 MG 0.02568 1.00 Tween-80 1310 168.2 MG 0.1284 5.00 Denatured ethanol: 2 mL Deionized water: 2 mL

Dissolve Tween 80 and tadalafil in a 5:1 molar ratio in 85% ethanol and stir the solution for about 30 minutes, at which time it appears as a slightly turbid solution. Dry the solution as described previously. After drying, a transparent viscous liquid gel is formed.

In step 2, the gel was dissolved in water and stirred at room temperature for 30 minutes. It should be noted that after the first 2-3 minutes, the solution became clear and homogeneous, with no precipitate. However, after 3 minutes, the solution slowly became turbid, eventually becoming a white and turbid solution at a pH of about 4.6. The pH was adjusted to about 3.0 using 50 μL of 0.1 N HCl. No visible changes occurred in the solution. When the white turbid solution (10-12 mg of drug complex in 0.5 mL D2O was used in all cases) was analyzed by NMR, a trace peak was observed, indicating that some complex had been formed, but its amount could not be determined. However, the peak indicates a solubility shift when an acid is used.

Another experiment was performed using a 1:10 ratio of tadalafil to surfactant as follows.

As before, 85% ethanol was added to a flask with tadalafil and poloxamer 188 (P-188) surfactant in a 1:10 ratio. Material Molecular weight weight Millimole Equivalent Tadalafil 389.4 10 MG 0.02568 1.00 P-188 8,400 215.7 MG 0.02568 10.00 Denatured ethanol: 2 mL Deionized water: 2 mL

85% ethanol was stirred with tadalafil and P-188 for 30 minutes. The reaction mixture became a white, turbid solution with visible solid particles. The solution was heated to about 45°C and a clear, homogeneous solution was produced within 2 to 3 minutes. The reaction mixture was cooled to room temperature and stirred for 10 minutes; it remained clear and homogeneous. The solution was then dried as described above.

The dried mixture was dissolved in water and formed a turbid solution with a pH of about 6.1. When the mixture was heated to 60°C, no change in the white turbid solution was observed. The solution was cooled to room temperature with stirring, and 200 μL of 0.1 N HCl was added to adjust the pH to about 2.0. However, the white turbid solution did not change. The mixture was then heated to 60°C, but again no change in the appearance of the solution was observed. NMR analysis indicated that no complex was formed.

Another experiment was performed using a 1:10:5 molar ratio of tadalafil:P188:stevioside in 85% (denatured) ethanol as follows. Material Molecular weight weight Millimole Equivalent Tadalafil 389.4 10 MG 0.02568 1.00 P-188 8,400 161.7 MG 0.02568 10.00 Stevioside 804.87 103.3 0.1284 5.00 Denatured ethanol: 3 mL Deionized water: 3 mL

Tadalafil and stevioside were dissolved in 85% ethanol and stirred for about 30 minutes; a white turbid solution was observed. The turbid solution was heated to 60°C. The reaction mixture was cooled to room temperature, and P-188 was added in one portion and stirred for 0.5 hours, with no change in the solution. The solution was then heated to 60°C, but no change in the solution was observed. 99.5% methanol (2.0 mL) was added and heated to 60°C, but no visible change in the white turbid solution was observed. 2.0 mL of 99.5% methanol was added to 3 mL of the mixture; the solution was then heated to 60°C, with no change in the white turbid solution. The solution was then dried as previously described.

To the dried mixture was added 3 mL of water and stirred for about 30 minutes; the mixture formed a white turbid solution. The solution was heated to 60°C, but this did not change the appearance of the solution. The heated solution was cooled to room temperature, and then 200 μL of 0.1 N citric acid was added to adjust the pH to about 3.0. Addition of citric acid did not change the appearance of the solution. The solution containing citric acid was heated to 90°C with stirring, but at least a change in the appearance of the solution was produced. When analyzed by NMR, a low intensity drug peak evidenced complex formation. The change in polarity due to the addition of acid improves complex formation and therefore improves solubility.

Another experiment was performed using a 1:5 molar ratio of drug to Tween 20 as follows. Material Molecular weight weight Millimole Equivalent Tadalafil 389.4 10 MG 0.02568 1.00 T20 1228 161.7 MG 0.1284 5.00 Denatured ethanol: 2 mL Deionized water: 2 mL

Tadalafil and Tween 20 (T20) were dissolved in 85% ethanol and stirred for about 30 minutes. The compound was observed to slowly form a clear homogeneous solution. The solution mixture was dried using the method described previously.

The dried mixture was then dissolved in 2.0 mL of water for 30 minutes, where it formed a white turbid solution with solids still visible in the solution. The mixture was then heated to 60°C with no change in appearance. NMR was performed on approximately 0.5 mL of the mixture, but only low peaks were observed at best, again indicating poor complex formation when a surfactant was used.

The remainder was cooled to room temperature and 10 mg of citric acid monohydrate was added to bring the pH to about 2.5. The solution remained white and turbid. The solution was then heated to 60°C, but no appearance change was observed. NMR revealed only low intensity drug peaks, indicating that some drug formed complexes.

Another experiment was performed using 1:20:5 tadalafil:glycerol:stevioside as follows. Material Molecular weight weight Millimole Equivalent Tadalafil 389.4 10 MG 0.02568 1.00 glycerin 92.09 23.64 MG 0.5136 20.00 Stevioside 804.87 103.3 0.1284 5.00 Denatured ethanol: 3 mL Deionized water: 3 mL

Tadalafil, glycerol and stevioside were added to a flask with 3.0 mL of 85% ethanol added. The mixture was stirred at room temperature for 30 minutes, forming a cloudy solution with visible particles present. 100 μL of ACS grade methanol was added and stirred for 20 minutes, and the solution became clear and homogeneous. The clear mixture was dried as previously described and a white powder was produced.

The dried mixture was dissolved in 3.0 mL of water and stirred at room temperature for about 30 minutes. A white turbid solution with a pH of 5.8 was formed. 0.1 NaOH solution was added to 1.5 mL of the mixture to adjust the final pH to about 7.4. This solution remained a white turbid solution. When detected by NMR, no drug peak was observed, which would indicate the formation of a complex between tadalafil and another component.

To another 1.5 mL portion, 10 mg of citric acid monohydrate was added and stirred at room temperature for about 30 minutes. The final solution had a pH of about 3.0. When evaluated by NMR, only a low intensity drug peak (about 2-3%) was observed. The acid appeared to improve complex formation and solubility.

Another experiment was performed using a 1:30:5 molar ratio of tadalafil:glycerol:stevioside as follows. Material Molecular weight weight Millimole Equivalent Tadalafil 389.4 10 MG 0.02568 1.00 glycerin 92.09 70.9 MG 0.7704 30.00 Stevioside 804.87 103.3 0.1284 5.00 ACS grade methanol: 3 mL Deionized water: 3 mL

Tadalafil and stevioside were dissolved in 3.0 mL of methanol (ACS grade ≥99.5% methanol, Sigma Aldrich) and stirred at room temperature for about 30 minutes to produce a white turbid solution. 50 μL of 85% ethanol was added and the mixture was stirred for another 20 minutes at about 30°C. The mixture became less white and more turbid. At this time, the mixture was dried as previously described.

The dry mixture was then dissolved in 3.0 mL of water and stirred for about 30 minutes. The pH of the mixture was about 5.8. To this solution was added 20 mg of citric acid monohydrate to lower the pH to about 3.0. A white turbid reaction was seen. NMR analysis revealed some low peaks, indicating complex formation. The experiment indicated that by lowering the solution pH, drug solubility was improved and thus complex formation was improved. Example 32 - Vardenafil Hydrochloride and Stevioside

In this experiment, a complex was attempted using vardenafil hydrochloride, stevioside, denatured ethanol, and water as follows. It is known that vardenafil hydrochloride is poorly soluble in water (0.11 mg/mL water). Although it is soluble in DMSO at 28°C, it is still solid at 22°C, and it is insoluble in chloroform. Material Molecular weight weight Millimole Equivalent Vardenafil hydrochloride 525.1 5 MG 0.00952 1.00 Stevioside 804.87 76.6 MG 0.09522 10.00 Ethanol: Denatured Water: Deionized

Vardenafil hydrochloride and stevioside were readily dissolved in 2.0 mL of denatured ethanol at a 1:10 molar ratio at room temperature to produce a clear solution. The reaction mixture was stirred for about 30 minutes.

The ethanol was removed by drying at 35°C as previously described until no weight change was observed. The powder was then dissolved in 2.0 mL of water and a clear solution resulted. When evaluated by NMR, a peak was observed corresponding to the formation of a complex between the sugar and vardenafil hydrochloride and the complex had 100% solubility. Example 33 - Alprostadil - Stevioside

In this experiment, an attempt was made to form a complex using alprostadil, stevioside, denatured ethanol and water as follows. Alprostadil is soluble in DMSO. Alprostadil has the chemical name: (1R,2R,3R)-3-hydroxy-2-[(E)-(3S)-3-hydroxy-1-octenyl]-5-oxocyclopentaneheptanoic acid and is also known as prostaglandin E1. Alprostadil is considered to be insoluble in water. Material Molecular weight weight Millimole Equivalent VITAROS 354.48 5 MG 0.01411 1.00 Stevioside 804.87 113 MG 0.14105 10.00 Ethanol: Denatured Water: Deionized

Both alprostadil and stevioside were readily dissolved in 2.0 mL of denatured ethanol at a 1:10 molar ratio at room temperature to produce a clear homogeneous solution (pH of about 4.9). The reaction mixture was stirred for about 30 minutes.

The ethanol was removed by drying at 35°C as previously described until no weight change was observed. The powder was then dissolved in 2.0 mL of water and a clear homogeneous solution (pH of about 5.8) was produced. When evaluated by NMR, a peak was observed corresponding to the formation of a complex between the sugar and alprostadil and the complex had 100% solubility.

In some cases, moderately soluble compounds can be made more soluble by complexing with a sugar as defined herein in the same ratios as the sugar and compound described herein. This is particularly important for the solubility of topically applied compounds because the compound is transported across the skin barrier for absorption in the body. For example, sildenafil has moderate solubility, but this can be increased by the methods used herein. Without being bound by any theory, it is believed that as the molar ratio of sugar to moderately soluble drug increases, the solubility of the resulting complex approaches the solubility of the sugar alone because, due to the presence of the sugar in the complex, the complex will have a greater solubility than the drug alone. Example 34 - Avanafil - Stevioside

In this experiment, avanafil and stevioside were tested at a 1:10 molar ratio in denatured ethanol as follows. Avanafil is soluble in DMSO. Avanafil, sildenafil, tadalafil, vardenafil, and udenafil are all PDE5 inhibitors. Material Molecular weight weight Millimole Equivalent Avanafil 483.95 5 MG 0.01033 1.00 Stevioside 804.87 83.15 MG 0.10332 10.00 Ethanol: Denatured Water: Deionized

The compound slowly dissolved in about 15 to 20 minutes with continuous stirring for 30 minutes. The compound eventually formed a clear and homogeneous solution with a pH of about 5.2. The solution was dried to remove ethanol until no further weight change was observed.

The dry powder was dissolved in 2.0 mL of water with stirring as described previously and formed a clear homogeneous solution with a pH of about 6.2. NMR showed complex formation and 100% dissolution of the compound. Example 35 - Udenafil - Stevioside

In this experiment, udenafil and stevioside were dissolved in denatured ethanol at a molar ratio of 1:10 as follows. Udenafil is known to be soluble in DMSO. It has a water solubility of approximately 0.0798 mg/mL. Material Molecular weight weight Millimole Equivalent Udenafil 516.66 5 MG 0.00968 1.00 Stevioside 804.87 77.9 MG 0.0968 10.00 Ethanol: Denatured Water: Deionized

When dissolved in 2.0 mL of 85% ethanol, both compounds were observed to form a clear, colorless, homogeneous solution after stirring for 30 minutes. The solution had a pH of approximately 5.5. The solution was dried to a powder as described previously.

The powder was dissolved in 2.0 mL of water and a clear solution was formed under stirring. However, after 1 hour, white particles began to form. NMR showed that a complex was formed, making the udenafil and stevioside complex soluble.

Thus, in one embodiment, there is provided a method for increasing the water solubility of a moderately soluble compound, the method comprising causing the compound to form a stable complex with a sugar as defined herein.

The following are examples showing various methods and the composites formed by these methods.

Example 1.       A water-soluble aggregate comprising a sugar and a poorly water-soluble drug, the aggregate comprising: a molar ratio of up to about 5 moles of the sugar per mole of the poorly water-soluble drug, wherein the sugar is one or more of the following: rubusoside, dulcoside B, dodecyl-β-D-maltoside, stevioside or leucoside A, with the proviso that the water-soluble aggregate increases the water solubility of the poorly soluble drug by at least five (5) times at 20°C compared to the water solubility of the drug not in the water-soluble aggregate; and with the proviso that the maximum amount of the sugar in a daily unit dose of the aggregate does not exceed about 10 mg/kg.

Example 2. A water-soluble aggregate as described in Example [1], wherein the sugar is rubusoside.

Embodiment 3. The water-soluble aggregate of embodiment [1] or [2], wherein the poorly water-soluble drug is one or more of the following: sildenafil, tadalafil, vardenafil, avanafil or a pharmaceutically acceptable salt of any one of them.

Embodiment 4. The water-soluble aggregate of any one of Embodiments [1] or [3], wherein the sugar is rubusoside, leucoside A, dodecyl-β-D-maltoside, dulcoside B or stevioside.

Embodiment 5.       The water-soluble aggregate of any one of embodiments [1], [3] or [4], wherein the amount of the sugar in the daily unit dose does not exceed 5 mg/kg.

Embodiment 6.       The water-soluble aggregate of any one of embodiments [1], [3] or [4], wherein the amount of the sugar in the daily unit dose does not exceed about 280 mg.

Embodiment 7.       The water-soluble aggregate of any one of embodiments [1], [3] or [4], wherein the water-soluble aggregate comprises a molar ratio of about 2 to about 5 moles of the sugar per mole of the poorly water-soluble drug.

Embodiment 8. A water-soluble aggregate as in any one of embodiments [1], [3] or [4], wherein the water-soluble aggregate comprises a molar ratio of about 2 to about 4.5 moles of the sugar per mole of the poorly water-soluble drug.

Example 9. The water-soluble aggregate of Example 8, wherein the water-soluble aggregate comprises a molar ratio of about 3 moles of the sugar per mole of the poorly water-soluble drug.

Embodiment 10. The water-soluble aggregate of any of the above embodiments, wherein the water-soluble aggregate is stable in water at pH 8.5 for at least 2 hours.

Embodiment 11. The water-soluble aggregate of any of the above embodiments, wherein the water-soluble aggregate is stable in water at pH 4 for at least 2 hours.

Embodiment 12. A dry form of the water-soluble aggregate of any of the above embodiments, wherein the dry form is stable at 30°C for at least 90 days.

Embodiment 13. The water-soluble aggregate of any of the above embodiments, wherein the water-soluble aggregate is in the form of powder, tablet, orally disintegrating tablet, capsule, liquid, gel, film, buccal tablet, effervescent powder or effervescent tablet, emulsion, or formulated for parenteral administration.

Embodiment 14. The water-soluble aggregate according to any one of the above embodiments, wherein the formulation for parenteral administration is administered intradermally, subcutaneously, intramuscularly, intraperitoneally or intravenously.

Embodiment 15. The water-soluble aggregate of any one of the above embodiments, wherein the water-soluble aggregate is in the form of a 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.

Example 16. A water-soluble aggregate comprising a sugar and a poorly water-soluble drug, the water-soluble aggregate comprising: a molar ratio of up to about 3 moles of the sugar per mole of the poorly water-soluble drug, wherein the sugar is one or more of the following: rubusoside, leucoside A, dulcoside B, dodecyl-β-D-maltoside (DDM) or stevioside; wherein the water-soluble aggregate is stable in water at pH 8.5 and pH 4.0 for at least 2 hours, respectively; subject to the condition that the water-soluble aggregate increases the water solubility of the poorly water-soluble drug at 20°C by at least five (5) times compared to the water solubility of the poorly water-soluble drug not in the water-soluble aggregate; and subject to the condition that the maximum amount of the sugar in a daily unit dose of the water-soluble aggregate does not exceed about 280 mg.

Embodiment 17. A method for preparing a water-soluble aggregate comprising a sugar and a poorly water-soluble drug, the method comprising the following steps: In at least 85% ethanol, the sugar and the poorly water-soluble drug are blended at a molar ratio of about 2 to about 5 moles of the sugar per mole of the poorly water-soluble drug until dissolved, thereby forming a water-soluble aggregate, wherein the formation of the water-soluble aggregate can be determined by nuclear magnetic resonance spectroscopy, and wherein the sugar is one or more of the following: rubusoside, leucoside A, dulcoside B, dodecyl-β-D-maltoside (DDM) or stevioside; and wherein the blending step is optionally carried out under a pharmaceutically acceptable acid; and Optionally drying the water-soluble aggregate.

Embodiment 18. The method of Embodiment 17, wherein the sugar is rubusoside or stevioside.

Embodiment 19. The water-soluble aggregate of any one of embodiments [17] or [18], wherein the poorly water-soluble drug is one or more of the following: sildenafil, tadalafil, vardenafil, avanafil, or a pharmaceutically acceptable salt thereof.

Embodiment 20. The method according to any one of embodiments [17] to [19], further comprising drying the water-soluble aggregate.

Embodiment 21. The method of embodiment [20], wherein the dried water-soluble aggregate is redissolved in a liquid.

Embodiment 22. The method of embodiment [17], wherein the blending step is carried out in the presence of a sufficient amount of a pharmaceutically acceptable acid to dissolve the reaction mixture and make it homogeneous and clear.

Embodiment 23. The method of embodiment [22], wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, 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.

Embodiment 24. The method of embodiment [17], wherein the formed water-soluble aggregates contain a molar ratio of about 2 to about 5 moles of the sugar per mole of the poorly water-soluble drug.

Embodiment 25. The method according to any one of embodiments [17] to [24], wherein the sugar is rubusoside or stevioside.

Embodiment 26. The method of any one of embodiments [17] to [25], wherein the formed water-soluble aggregates contain a molar ratio of about 2 to about 4.5 moles of the sugar per mole of the poorly water-soluble drug.

Embodiment 27. The method according to embodiment [26], wherein the sugar is rubusoside or stevioside.

Embodiment 28. The method of embodiment [24], wherein the formed water-soluble aggregates contain a molar ratio of about 3 moles of the sugar per mole of the poorly water-soluble drug.

Embodiment 29. The method according to embodiment [28], wherein the sugar is rubusoside or stevioside.

Embodiment 30. The method of embodiment [17], wherein the formed water-soluble aggregates are stable in water at pH 8.5 for at least 2 hours.

Embodiment 31. The method of embodiment [17], wherein the formed water-soluble aggregates are stable in water at pH 4 for at least 2 hours.

Embodiment 32. The method of embodiment [20] further comprises drying the water-soluble aggregate by freeze drying or lyophilization.

Embodiment 33. The method of embodiment [32], wherein the dried water-soluble aggregate is formulated into a pellet or a pharmaceutically acceptable liquid.

Example 34. A water-soluble complex comprising a poorly water-soluble drug and a sugar (DTG), wherein the drug has a hydrogen bond from the poorly water-soluble drug to the sugar, thereby forming a water-soluble complex of formula (I): [ DTG ] _pdrug (I), wherein p is a molar ratio of up to about 20 moles of a sugar (DTG) per mole of the drug, wherein the sugar is one or more of rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, leucoside A, leucoside B, leucoside D, stevioside, stevia, n-octylglucose, n-dodecyl-β-D-maltoside, advantame®, neotame, thaumatin, saccharin, sucralose, steviol glycosides, monk fruit, aspartame, acesulfame potassium, or psicose, wherein the drug is an erectile dysfunction drug, and wherein the water-soluble complex increases the water solubility of the compound at 20° C. by at least five (5) times compared to the water solubility of the compound not in the water-soluble complex.

Example 35. A water-soluble complex as in Example [34], comprising a molar ratio of up to about 5 moles of a sugar per mole of the poorly water-soluble drug, wherein the sugar is one or more of the following: rubusoside, dulcoside B, dodecyl-β-D-maltoside, stevioside or leucoside A, with the proviso that the water-soluble complex increases the water solubility of the poorly water-soluble drug by at least five (5) times at 20°C as compared to the water solubility of the drug not in the water-soluble complex; and with the proviso that the maximum amount of the sugar in a daily unit dose of the complex does not exceed about 10 mg/kg.

Embodiment 36. The water-soluble complex of embodiment [34] or [35], wherein the poorly water-soluble drug is one or more of the following: alprostadil, sildenafil, tadalafil, vardenafil, avanafil, or a pharmaceutically acceptable salt or polymorph thereof.

Embodiment 37. The water-soluble complex of any one of embodiments [34] to [36], wherein the sugar is rubusoside, leucoside A, dodecyl-β-D-maltoside, dulcoside B or stevioside.

Embodiment 38. The water-soluble complex of any one of embodiments [35] to [37], wherein the amount of the sugar in the daily unit dose does not exceed 5 mg/kg.

Embodiment 39. The water-soluble complex of technical solution 5, wherein the amount of the sugar in the daily unit dose does not exceed about 280 mg.

Embodiment 40. The water-soluble complex of any one of embodiments [34] to [39], wherein the water-soluble complex comprises a molar ratio of about 2 to about 5 moles of the sugar per mole of the drug.

Embodiment 41. The water-soluble complex of any one of embodiments [34] to [39], wherein the water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of the sugar per mole of the poorly water-soluble drug.

Embodiment 42. The water-soluble complex of embodiment [41], wherein the water-soluble complex comprises a molar ratio of about 3 moles of the sugar per mole of the drug.

Embodiment 43. The water-soluble complex of any one of Embodiments [34] to [42], wherein the water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

Embodiment 44. The water-soluble complex of any one of embodiments [34] to [42], wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours.

Embodiment 45. A dry form of the water-soluble complex of any one of Embodiments [34] to [44], wherein the dry form is stable at 30°C for at least 90 days.

Embodiment 46. The water-soluble complex of any one of Embodiments [34] to [44], wherein the water-soluble complex is in a form for oral administration, such as powder, tablet, orally disintegrating tablet, capsule, liquid, gel, film, buccal tablet, effervescent powder or effervescent tablet or emulsion, or is formulated for parenteral administration.

Embodiment 47. The water-soluble complex of Embodiments [34] to [46], wherein the formulation for parenteral administration is administered intradermally, subcutaneously, intranasally, intramuscularly or intraperitoneally.

Embodiment 48. The water-soluble complex of any one of embodiments [34] to [45], wherein the water-soluble complex is in the form of a 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.

Example 49. A water-soluble complex comprising a sugar and a poorly water-soluble drug, the water-soluble complex comprising: a molar ratio of up to about 3 moles of the sugar per mole of the poorly water-soluble drug, wherein the sugar is one or more of the following: rubusoside, leucoside A, dulcoside B, dodecyl-β-D-maltoside (DDM) or stevioside; wherein the water-soluble complex is stable for at least 2 hours in water at about pH 8.5 and about pH 4.0, respectively; with the proviso that the water-soluble complex increases the water solubility of the poorly water-soluble drug at 20°C by at least five (5) times compared to the water solubility of the poorly water-soluble drug not in the water-soluble complex; and The limiting condition is further that the maximum amount of the sugar in the daily unit dose of the water-soluble complex does not exceed about 280 mg.

Embodiment 50. A method for preparing a water-soluble complex, the water-soluble complex comprising a sugar and a poorly water-soluble drug, the method comprising the following steps: In at least 85% ethanol, the sugar and the poorly water-soluble drug are blended at a molar ratio of about 1 to about 20 moles of the sugar per mole of the poorly water-soluble drug until dissolved, thereby forming the water-soluble complex, wherein the formation of the water-soluble complex can be determined by nuclear magnetic resonance (NMR) spectroscopy, and wherein the sugar is one or more of the following: rubusoside, leucoside A, dulcoside B, dodecyl-β-D-maltoside (DDM) or stevioside; and wherein the blending step is carried out in a pharmaceutically acceptable acid, base, buffer or surfactant as appropriate; and Dry the water-soluble complex as necessary.

Embodiment 51. The method according to embodiment [50], wherein the sugar is rubusoside or stevioside.

Embodiment 52. The water-soluble complex of any one of Embodiments [50] to [51], wherein the poorly water-soluble drug is one or more of the following: alprostadil, sildenafil, tadalafil, vardenafil, avanafil, or a pharmaceutically acceptable salt thereof.

Embodiment 53. The method of embodiment [50] further comprises drying the water-soluble complex.

Embodiment 54. The method of embodiment [53], wherein the dried water-soluble complex is redissolved in water, optionally in the presence of a pharmaceutically acceptable acid, base, buffer or surfactant.

Embodiment 55. The method of embodiment [50], wherein the mixing step is carried out in the presence of a sufficient amount of a pharmaceutically acceptable acid to solubilize the reaction mixture and make it homogeneous and clear.

Embodiment 56. The method of embodiment [55], wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic 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.

Embodiment 57. The method of embodiment [50], wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 20 moles of the sugar per mole of the poorly water-soluble drug.

Embodiment 58. The method according to embodiment [57], wherein the sugar is rubusoside or stevioside.

Embodiment 59. The method of embodiment [50], wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 10 moles (eg, 4.5 moles) of the sugar per mole of the poorly water-soluble drug.

Embodiment 60. The method according to embodiment [59], wherein the sugar is rubusoside or stevioside.

Embodiment 61. The method of embodiment [57], wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 5 moles of the sugar per mole of the poorly water-soluble drug.

Embodiment 62. The method of embodiment [61], wherein the sugar is rubusoside or stevioside.

Embodiment 63. The method of embodiment [50], wherein the formed water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

Embodiment 64. The method of embodiment [50], wherein the formed water-soluble complex is stable in water at pH 4 for at least 2 hours.

Embodiment 65. The method of embodiment [53], wherein the method further comprises drying the water-soluble complex by freeze drying or lyophilization.

Embodiment 66. The method of embodiment [65], wherein the dried water-soluble complex is formulated into pills or a pharmaceutically acceptable liquid.

Figure 1 depicts potential hydrogen bonding and/or inclusion complex formation between rubusoside and sildenafil (e.g., VIAGRA®). A total of nine intermolecular hydrogen bonds (e.g., H--O; H--N; H--S; and NH--O) may exist between rubusoside and sildenafil. Sildenafil has a MW of 474.58 and elemental analysis of C, 55.68; H, 6.37; N, 17.71; O, 13.48; and S, 6.76. The possible structures and number of hydrogen bonds are based on the original structural model and post-bonding NMR analysis.

Claims (33)

A water-soluble complex comprising a poorly water-soluble drug and a sugar (DTG), wherein the drug has a hydrogen bond between the drug and the sugar to form a water-soluble complex of formula (I): [ DTG ] _pdrug (I), wherein p is a molar ratio of up to about 20 moles of the sugar (DTG) per mole of the drug, wherein the sugar is one or more of the following: rubusoside, dulcoside A, dulcoside B, sucrose, D-fructose, sucralose, rebaudioside A, leucoside B, leucoside D, stevioside, stevia, n-octylglucose, n-dodecyl-β-D-maltoside, advantame®, neotame, thaumatin, saccharin, sucralose, steviol glycoside, Lou Han Guo, aspartame, acesulfame potassium, or allulose, wherein the drug is an erectile dysfunction drug, and with the proviso that the water-soluble complex increases the water solubility of the compound at 20° C. by at least five (5) times compared to the water solubility of the compound not in the water-soluble complex. A water-soluble complex as claimed in claim 1, comprising a molar ratio of up to about 5 moles of a sugar per mole of the poorly water-soluble drug, wherein the sugar is one or more of the following: rubusoside, dulcoside B, dodecyl-β-D-maltoside, stevioside, or leucoside A, with the proviso that the water-soluble complex increases the water solubility of the poorly soluble drug at 20°C by at least five (5) times as compared to the water solubility of the drug not in the water-soluble complex; and with the further proviso that the maximum amount of the sugar in a daily unit dose of the complex does not exceed about 10 mg/kg. The water-soluble complex of claim 1 or claim 2, wherein the poorly water-soluble drug is one or more of the following: alprostadil, sildenafil, tadalafil, vardenafil, avanafil, or a pharmaceutically acceptable salt or polymorph thereof. The water-soluble complex of any one of claims 1 to 3, wherein the sugar is rubusoside, leucoside A, dodecyl-β-D-maltoside, dulcoside B, or stevioside. The water-soluble complex of any one of claims 2 to 4, wherein the amount of the sugar in the daily unit dose does not exceed 5 mg/kg. The water-soluble complex of claim 5, wherein the amount of the sugar in the daily unit dose does not exceed about 280 mg. The water-soluble complex of any one of claims 1 to 6, wherein the water-soluble complex comprises a molar ratio of about 2 to about 5 moles of the sugar per mole of the drug. The water-soluble complex of any one of claims 1 to 6, wherein the water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of the sugar per mole of the poorly water-soluble drug. The water-soluble complex of claim 8, wherein the water-soluble complex comprises a molar ratio of about 3 moles of the sugar per mole of the drug. The water-soluble complex of any one of claims 1 to 9, wherein the water-soluble complex is stable in water at pH 8.5 for at least 2 hours. The water-soluble complex of any one of claims 1 to 9, wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours. A dry form of the water-soluble complex of any one of claims 1 to 11, wherein the dry form is stable at 30°C for at least 90 days. The water-soluble complex of any one of claims 1 to 12, wherein the water-soluble complex is in a form for oral administration, such as powder, tablet, orally disintegrating tablet, capsule, liquid, gel, film, buccal tablet, effervescent powder or effervescent tablet, or emulsion, or is formulated for parenteral administration. The water-soluble complex of claim 13, wherein the formulation for parenteral administration is administered intradermally, subcutaneously, intranasally, intramuscularly or intraperitoneally. The water-soluble complex of any one of claims 1 to 12, wherein the water-soluble complex is in the form of a 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. A water-soluble complex comprising a sugar and a poorly water-soluble drug, the water-soluble complex comprising: a molar ratio of about 3 moles of the sugar per mole of the poorly water-soluble drug, wherein the sugar is one or more of the following: rubusoside, leucoside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; wherein the water-soluble complex is stable for at least 2 hours in water at about pH 8.5 and about pH 4.0; subject to the proviso that the water-soluble complex increases the water solubility of the poorly water-soluble drug at 20°C by at least five (5) times as compared to the water solubility of the poorly water-soluble drug not in the water-soluble complex; and subject to the proviso that the maximum amount of the sugar in a daily unit dose of the water-soluble complex does not exceed about 280 mg. A method for preparing a water-soluble complex comprising a sugar and a poorly water-soluble drug, the method comprising the following steps: In at least 85% ethanol, the sugar and the poorly water-soluble drug are blended at a molar ratio of about 2 to about 5 moles of the sugar per mole of the poorly water-soluble drug until dissolved, thereby forming the water-soluble complex, wherein the formation of the water-soluble complex can be determined by nuclear magnetic resonance (NMR) spectroscopy, and wherein the sugar is one or more of the following: rubusoside, leucoside A, dulcoside B, dodecyl-β-D-maltoside (DDM), or stevioside; and wherein the blending step is performed using a pharmaceutically acceptable acid, base, buffer or surfactant as appropriate; and Optionally drying the water-soluble complex. The method of claim 17, wherein the sugar is rubusoside or stevioside. The method of any one of claim 17 or 18, wherein the poorly water-soluble drug is one or more of the following: alprostadil, sildenafil, tadalafil, vardenafil, avanafil, or a pharmaceutically acceptable salt thereof. The method of claim 17, further comprising drying the water-soluble complex. The method of claim 20, wherein the dried water-soluble complex is redissolved in water together with a pharmaceutically acceptable acid, base, buffer or surfactant as appropriate. The method of claim 17, wherein the mixing step is carried out in the presence of a sufficient amount of a pharmaceutically acceptable acid to dissolve and make the reaction mixture homogeneous and clear. The method of claim 22, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic 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. The method of claim 17, wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 5 moles of the sugar per mole of the poorly water-soluble drug. The method of claim 24, wherein the sugar is rubusoside or stevioside. The method of claim 17, wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of the sugar per mole of the poorly water-soluble drug. The method of claim 26, wherein the sugar is rubusoside or stevioside. The method of claim 24, wherein the formed water-soluble complex comprises a molar ratio of about 3 moles of the sugar per mole of the poorly water-soluble drug. The method of claim 28, wherein the sugar is rubusoside or stevioside. The method of claim 17, wherein the formed water-soluble complex is stable in water at pH 8.5 for at least 2 hours. The method of claim 17, wherein the formed water-soluble complex is stable in water at pH 4 for at least 2 hours. The method of claim 20, wherein the method further comprises drying the water-soluble complex by freeze drying or lyophilization. The method of claim 32, wherein the dried water-soluble complex is formulated into pills or a pharmaceutically acceptable liquid.