Compositions and methods for improving solubility of insulin, insulin analogs, and a1c or glucose regulating compounds

Abstract

A method for improving the solubility of a pharmaceutical compound is disclosed, wherein the pharmaceutical compound is insulin, a natural insulin variant, an insulin variant or insulin analog, a GLP-1 agonist, a GIP agonist, a glucagon agonist, an amylin agonist or an incretin mimic. The method involves using a non-nutritive sugar, such as raspberry glycoside, neohesperidin A, dulcitin B, dodecyl-β-D-maltodextrin (DDM), or carhariside, or any combination thereof, in the presence of a solvent such as ethanol or a mixture thereof, followed by removal of the solvent by drying and re-solubilization to generate a water-soluble complex. The complex formed using the disclosed method is also described.

Description

Technical Field

[0001] Disclosed are water-soluble complexes of non-nutritive sugars such as diterpenoid glycosides (DTG), diterpenoid-disaccharides (“DDG”) or other non-nutritive sugars and / or surfactants with pharmaceutical compounds (which may or may not be poorly soluble) that are involved in regulating blood glucose and / or A1C levels in subjects, wherein the complex significantly enhances the solubility of the compounds. Methods for preparing such complexes and pharmaceutical compositions comprising such water-soluble sugar-drug complexes are also disclosed.

[0002] Citation of relevant applications

[0003] This international PCT application claims the interests and priorities of U.S. Provisional Applications 63 / 539,788, 63 / 613,443, 63 / 662,263 and 63 / 673,012, filed on September 21, 2023, December 21, 2023, June 20, 2024 and July 18, 2024, respectively, the contents of which are incorporated herein by reference for all purposes.

[0004] background

[0005] The solubility of many compounds plays a crucial role in their commercial applications, particularly in the pharmaceutical industry. Compound solubility is significant in the efficacy of a compound as a drug, especially in many essential pharmacokinetic properties. Poor drug solubility can directly lead to insufficient uptake, C60, and other adverse reactions. max Poor properties (e.g., maximum blood concentration and time to reach maximum blood concentration). If the drug cannot dissolve sufficiently, it may not be completely absorbed into the subject's bloodstream, leading to C... max Inadequate and ineffective (e.g., Ganesan et al., “Solubility: a speed-breaker on the drug discovery highway,”) Bioequiv. Availab . 3(3): 56-8, 2017, Editorial).

[0006] Insulin is a fundamental medication for many patients with insulin-dependent diabetes mellitus; without it, these patients cannot control their blood sugar and ultimately die. Currently, human insulin is available from several manufacturers and, in all cases, must be refrigerated to prevent protein degradation. Conventional insulin is delivered by injection, which can be administered several times a day, increasing the risk of injection site infections. Recently, orally deliverable insulin has been introduced, exhibiting stable resistance to degradation in the gastrointestinal tract. A system that could potentially deliver oral insulin via the colon has been described (Martínez-López et al., “Arabinoxylans-Based Oral Insulin Delivery System Targeting the Colon: Simulation in a Human Intestinal Microbial Ecosystem and Evaluation in Diabetic Rats.”). Pharmaceuticals (Basel). 2022 Aug 26; 15(9): 1062). A recent review describes advances in material design for potential oral insulin delivery materials (Ji, K. et al., “Material design for oral insulin delivery”). Med-X 1 , 7 (2023)). However, there appears to be no long-acting oral insulin, especially of this kind that shows stability at room temperature for more than 24 hours.

[0007] The use of long-acting insulin to maintain basal drug levels in patients requires frozen insulin and injection administration. The ability to deliver long-acting insulin in an orally deliverable form, and without the need for refrigeration, at least for the day of administration, offers a significant improvement over currently available commercial insulin products.

[0008] A method is still needed to make drug compounds, including poorly soluble drug compounds such as insulin and insulin analogs (e.g., human insulin and human homologs, such as HUMALOG®), more significantly soluble in aqueous environments.

[0009] This article focuses on other compounds used to generate more soluble complexes that can lower blood glucose and / or A1C levels in subjects. These compounds include glucagon-like peptide-1 (GLP-1) agonists, as well as glucose-dependent islet-stimulating peptide (GIP) and GLP-1 / GIP dual agonists. Other compounds include amylin agonists and glucagon modulators. These agonists require improved solubility, regardless of whether they are in the free form, salt form, or another related form of the compound.

[0010] Overview

[0011] This document provides complexes (sometimes referred to as aggregates in related provisional applications) of one or more diterpenoid glycosides with pharmaceutical compounds, said diterpenoid glycosides including diterpenoid di-glycosides (DDG), said pharmaceutical compound being insulin or an insulin analog, and wherein the solubility of the complex is significantly enhanced compared to the pharmaceutical compound alone (e.g., not in the complex). The water-soluble complexes described herein use pharmaceutical compounds, which are typically pharmaceutical compounds having at least one heteroatom capable of forming hydrogen bonds with DTG, DDG, or other non-nutritive sugars (and optionally with surfactants in the complexes described herein). Without being bound by theory, it is conceivable that when sugars (and optionally surfactants in the complexes described herein) aggregate (e.g., coordinate) with pharmaceutical compounds, stable complexation (e.g., coordination) may occur through non-covalent hydrogen bonds and optional hydrophobic-hydrophobic interactions such as van der Waals forces. Insulin is characterized by being insoluble in water at physiological pH but dissolving relatively quickly in plasma. Insulin is known to form insoluble zinc-containing hexamers. The mature form of human insulin consists of two peptide chains – chain A and chain B – which are linked together by disulfide bonds (UniProt P01308 INS-HUMAN).

[0012] It is well known that the sugar moiety of DTG, DDG, or non-nutritive sugars contains multiple 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.), amino groups (e.g., glucosamine), or N-acetyl groups (e.g., N-acetylglucosamine), each capable of forming hydrogen bonds. The presence of such functional groups allows DTG, DDG, or non-nutritive sugars to participate in hydrogen bonding with pharmaceutical compounds containing at least one heteroatom, which can form hydrogen bonds with DTG, DD, or other non-nutritive sugars.

[0013] Unbound by any theoretical constraints, the focus is on a mode of action that utilizes multiple hydroxyl groups on sugar units in DTG, DDG, or other non-nutritive sugars to generate multiple aggregation and / or complexation sites between the hydroxyl functional groups of the sugar units in DTG or other non-nutritive sugars and the heteroatoms of the drug compound. These heteroatoms alone cannot generate sufficient adhesive forces to maintain a stable complex. Through aggregation, a cumulative amount of adhesion is achieved, thereby providing a stable complex. Furthermore, it is believed that diterpenoid glycosides and other listed sugars utilize hydrophobic-hydrophobic interactions with drug compounds that provide hydrophobic and hydrophilic binding element regions. It is further envisioned that these hydrophobic and hydrophilic regions will allocate to hydrophobic interactions, maintaining hydrophobic interactions within the complex while exhibiting hydrophilic interactions on the exterior, thus making the complex soluble in aqueous solutions.

[0014] Disclosed are water-soluble complexes of diterpenoid di-glycosides (“DDG”) with human insulin or insulin analogs, wherein the complex is capable of oral delivery to insulin-dependent patients and is a subset of DTG. The complex is stable at room temperature for at least about 24 hours, at least 48 hours, or at least 96 hours. In one embodiment, a method is provided for maintaining basal insulin levels in insulin (or insulin analogs)-dependent patients using the complex disclosed herein. In another embodiment, a method is provided in which the complex is used to control glycosylated hemoglobin in patients by maintaining basal levels of insulin or insulin analogs.

[0015] One embodiment discloses a water-soluble complex comprising a sugar (and optionally a surfactant in a complex as described herein) and a pharmaceutical compound, the water-soluble complex comprising: a molar ratio of up to about 12 moles of sugar per mole of pharmaceutical compound, wherein said sugar is one or more of rubusoside, dulcoside B, dodecyl-β-D-maltodextrin, stevioside, or rebaudioside A, provided that the water-soluble complex increases the water solubility of the pharmaceutical compound at 20°C by at least two (2), three (3), four (4), or five (5) times compared to the water solubility of the pharmaceutical compound not in the water-soluble complex; and further provided that the maximum amount of sugar in a daily unit dose of the water-soluble complex does not exceed about 10 mg / kg, wherein the drug compound is a peptide or small compound for lowering blood glucose and / or blood A1C in the subject, wherein the drug compound is insulin, insulin analog, natural insulin variant, GLP-1 receptor agonist, incretin mimic, GIP agonist, amylin agonist, glucagon agonist or a salt thereof.

[0016] When the drug compound in the water-soluble complex is an insulin analog, it can be any one of insulin lispro, insulin aspart, insulin glulisine, admelog, NPH insulin, insulin isophane, insulin glargine, insulin determir, or insulin degludec. The drug compound can also be an A1C-regulating drug compound. If the drug compound is insulin or an insulin analog, it can be rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or ultra-long-acting insulin. Typically, ultra-long-acting insulin reaches blood flow within 6 hours, does not reach peak flow, and lasts for approximately 36 minutes or longer (e.g., insulin glargine U-300, Toujeo). Long-acting insulin begins to work after 30 minutes to approximately 4 hours and lasts for up to 16-24 hours. Regular insulin is considered short-acting insulin; it typically takes effect within 1 hour of administration and reaches its peak effect approximately 2 to 4 hours after administration. Intermediate-acting insulin typically reaches the bloodstream approximately 2 to 4 hours after injection, reaches its peak effect approximately 12 hours later, and has an effective period of 12 to 18 hours. These insulins can be insulin analogs, natural insulin, or natural insulin known to those skilled in the art.

[0017] In another embodiment, when the pharmaceutical compound in the water-soluble complex is a GLP-1 receptor agonist, the GLP-1 receptor agonist is semaglutide, tirzepatide, amycretin, orforglipron, albiglutide, beinaglutide, cagrilintide, CagriSema, CT996, danuglipron, or fenofitoide. efinopegdutide), HM15211, lixisenatide, pemvidutide, retratrutide, SCO-094, survodutide, WK2735, mazdutide, PEG-profenatide (PEX168), liraglutide, dulaglutide, exenatide, or their salts, cocrystals, hydrates, solvates, or polymorphs.

[0018] In another embodiment, when the pharmaceutical compound in the water-soluble complex is a GIP agonist, the GIP agonist is HM15211, retatrutide, SCO-094, telpolide, WK2735, ZP6590 or its salts, cocrystals, hydrates, solvates or polymorphs.

[0019] In another embodiment, when the pharmaceutical compound in the water-soluble complex is a glucagon agonist, the glucagon agonist is affinoside, HM15211, mascara, pevitide, sovoglutide or its salts, cocrystals, hydrates, solvates or polymorphs.

[0020] In another embodiment, when the pharmaceutical compound in the water-soluble complex is an amylin agonist, the amylin agonist is AZD6234, caglitinide, CagriSema, CT388, a long-acting amylin agonist, amiklipine, ZP8396 or its salts, cocrystals, hydrates, solvates or polymorphs.

[0021] In one embodiment, the complex described herein can be represented by the following formula I:

[0022] DTG (including DTG, DDG, or other non-nutritive sugars / sweeteners) and pharmaceutical compounds (e.g., insulin or insulin analogs or A1C-regulating compounds) are as defined herein, and p The value is an integer from 1.5 to 12. This general formula may also include a surfactant. The surfactant is preferably a nonionic surfactant. The ratio of the drug to the nonionic surfactant can be 1:10, 1:5, and 1:0.5, or any 0.1 value of the surfactant between about 0.5 and 10.0.

[0023] As defined below, DTG, when referred to in the general formula as "DTG," includes diterpenoid di-glycosides (DDGs) and other non-nutritive sugars. Such DTGs include carabinin and raspberry glycosides, as well as other related compounds.

[0024] This article discloses and focuses on water-soluble complexes comprising a non-nutritive sugar (and / or a surfactant) and a pharmaceutical compound, the complex comprising: a molar ratio of up to about 12 moles of non-nutritive sugar per mole of pharmaceutical compound, wherein said sugar is one or more of raspberry glycoside, dulcitin B, dodecyl-β-D-maltodextrin, carhariin, or neohesperidin A, provided that the water-soluble complex increases the water solubility of the pharmaceutical compound at 20°C by at least two (2), three (3), four (4), or five (5) times compared to the water solubility of the drug not in the water-soluble complex; and further, provided that the maximum amount of sugar in a daily unit dose of the complex does not exceed about 10 mg / kg. The non-nutritive sugar used to prepare the water-soluble complex may be raspberry glycoside or carhariin.

[0025] Another type of water-soluble complex concerns pharmaceutical compounds selected from insulin, such as human insulin and its variants, i.e., insulin analogs. Exemplary insulins are those that have the desired pharmaceutical properties when administered to animals. Exemplary insulins include, but are not limited to, insulin lispro (e.g., Humalog®), insulin aspart (e.g., NovoLog™), bovine insulin, insulin degludec (e.g., Tresiba®), insulin detemir (e.g., Levemir®), insulin glargine (e.g., Lantus™), insulin glutathione (e.g., ApidraA®), insulin pork (e.g., Iletin® II), conventional insulin (e.g., Humulin® R), insulin porcine (e.g., vetsulin® / Caninsulin®), and protamine zinc insulin (e.g., Novolin® N). Other examples of commercially available products include HUMALOG®, HUMALOG 50 / 50™, HUMALOG 75 / 25™, HUMULIN 50 / 50™, HUMALIN 75 / 25™, HUMALIN L™, HUMALIN N™, HUMALIN®, HUMALINR U-500™, HUMALIN U™, ILETIN II LENTE™, ILETIN II NPH™, ILETIN II REGULAR™ LANTUS™, NOVOLIN 70 / 30™, NOVILIN N™, NOVILIN R™, NOVOLOG™, VELOSULIN BR™, and EXUBERA™. Lente insulin (vetsulin), ProZinc, or glargine insulin can be used in cats.

[0026] The water-soluble complexes of interest and the methods for preparing the complexes also involve the generation of complexes from GLP-1 agonists, GIP agonists, amylin agonists, incretin mimics and glucagon agonists, their salts, cocrystals, hydrates, polymorphs and solvates, as well as pharmaceutical compounds having various agonist activities.

[0027] Food passes through the large intestine very slowly, taking up to 36 hours. Without being bound by theory, it can be envisioned that the complex described herein, ingested along with food, enters the large intestine unaffected by the acidic environment of the stomach. Furthermore, without being bound by theory, it is thought that the improved solubility of the drug in its complex form might facilitate its transport within the body.

[0028] In some embodiments, the water-soluble complex is composed of a non-nutritive sugar selected from ADVANTAME®, NEOTAME®, thaumatin, saccharin, sucralose, LouHan Guo, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitin B, dodecyl-β-D-maltose glycoside, carhariin, or neohesperidin A. In other embodiments, the water-soluble complex is composed of a non-nutritive sugar selected from raspberry glycoside, neohesperidin A, dodecyl-β-D-maltose glycoside, dulcitin B, carhariin, or any combination thereof. Still in another embodiment, the complex can be formed using raspberry glycoside, dulcitin B, dodecyl-β-D-maltose glycoside, carhariin, or neohesperidin A, or combinations thereof. In another embodiment, the water-soluble complex uses raspberry glycoside, coixol, or a combination thereof.

[0029] In another embodiment, the amount of non-nutritive sugars in the daily unit dose administered to the subject does not exceed about 5 mg / kg of the subject's body weight. In another embodiment, the water-soluble complex contains no more than about 280 mg of non-nutritive sugars in the daily unit dose.

[0030] In one embodiment, the water-soluble complex comprises (in moles of the pharmaceutical compound) and a non-nutritive sugar (and optionally a surfactant in the complex as described herein); the molar ratio of pharmaceutical compound to non-nutritive sugar is about 1:1 to about 1:12, about 1:1 to about 1:10, or about 1:1 to about 1:5 moles. In one embodiment, the water-soluble complex comprises about 3.0 moles of non-nutritive sugar per mole of pharmaceutical compound, i.e., a molar ratio of about 1:3.

[0031] In another embodiment, the water-soluble complex comprises a molar ratio of about 2 to about 5 moles of non-nutritive sugar per mole of pharmaceutical compound, i.e., a molar ratio of pharmaceutical compound to non-nutritive sugar of about 1:2 to about 1:5.

[0032] In another embodiment, the water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of non-nutritive sugar per mole of pharmaceutical compound, i.e., a molar ratio of pharmaceutical compound to non-nutritive sugar of about 1:2 to about 1:4.5.

[0033] Another implementation focuses on the stability of the water-soluble complex in water at pH 8.5 for at least about 2 hours.

[0034] In another embodiment, the water-soluble complex is stable in water at pH 4 for at least about 2 hours.

[0035] Another implementation focuses on the stability of the water-soluble complex in its dried form at 30°C for at least 90 days.

[0036] Another implementation focuses on the water-soluble complex being stable at room temperature for approximately 24 hours. Yet another implementation focuses on the water-soluble complex not requiring refrigeration for at least 24 hours.

[0037] Another embodiment focuses on water-soluble complexes in the form of powders, tablets, orally disintegrating tablets, capsules, liquids, gels, films, lozenges, chewable pills or gummies, effervescent powders or tablets, or emulsions. Alternatively, the water-soluble complex can be formulated for parenteral administration and can be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, topically (e.g., transdermal patches, creams, lotions, or gels), or intravenously. Another embodiment focuses on formulating the water-soluble complex into films, effervescent powders or tablets, syrups, solutions, elixirs, emulsions, chewing gum, gummies, lollipops, sublingual drops, soft gels, or tinctures.

[0038] Another embodiment focuses on a water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, wherein the water-soluble complex comprises: a molar ratio of approximately 3 moles of non-nutritive sugar per mole of pharmaceutical compound, wherein the non-nutritive sugar is one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitidine B, dodecyl-β-D-maltodextrin, coixol, or neohesperidin A; wherein the water-soluble complex is stable in water for at least 2 hours at pH 8.5 and at pH 4.0; provided that the water-soluble complex increases the water solubility of the pharmaceutical compound at 20 °C by at least two (2) times, three (3) times, four (4) times, or five (5) times compared to the water solubility of the pharmaceutical compound not present in the water-soluble complex; and further provided that the maximum amount of non-nutritive sugar in a daily unit dose of the water-soluble complex does not exceed approximately 280 mg.

[0039] On the other hand, attention is focused on a method for preparing a water-soluble complex comprising a non-nutritive sugar (and optionally a surfactant in the complex as described herein) and a pharmaceutical compound (wherein the pharmaceutical compound may or may not be poorly water-soluble), the method comprising the steps of: mixing the non-nutritive sugar and the pharmaceutical compound in at least 85% ethanol (or at least 90% or 95%) at a molar ratio of about 1.0 to about 5.0 moles of sugar per mole of pharmaceutical compound until dissolved, thereby forming a water-soluble complex, wherein the water-soluble complex can be determined by nuclear magnetic resonance spectroscopy (NMR). The formation of this water-soluble complex, wherein the sugar is one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitin B, dodecyl-β-D-maltose glycoside, carhariin, or neohesperidin A, wherein the mixing step (step 1) is optionally carried out with a pharmaceutically acceptable acid in one or more solvents; the components of step 1 are dried, and step 2 comprises dissolving the components in water and optionally drying the water from the water-soluble complex. In another method, the non-nutritive sugar is raspberry glycoside, dulcitin B, dodecyl-β-D-maltose glycoside, carhariin, neohesperidin, or a group thereof. In another method, the sugar used in the method is raspberry glycoside, carhariin, or a combination thereof. The pharmaceutical compound (i.e., a pharmaceutical compound or a poorly soluble pharmaceutical compound) used in the method for preparing the water-soluble complex may be insulin or an A1C-regulating compound. The pharmaceutical compound can be any insulin, such as wild-type insulin (“regular insulin”) or any functional variant thereof, including naturally occurring variants and insulin analogs. Exemplary insulins include, but are not limited to, insulin lispro (e.g., Humalog®), insulin aspart (e.g., NovoLog™), bovine insulin, insulin degludec (e.g., Tresiba®), insulin detemir (e.g., Levemir®), insulin glargine (e.g., Lantus™), insulin glutalis (e.g., ApidraA®), insulin pork (e.g., Iletin® II), regular insulin (e.g., Humulin® R), insulin porcine (e.g., vetsulin), and protamine zinc insulin (e.g., Novolin® N).Other examples of commercially available products include HUMALOG®, HUMALOG 50 / 50™, HUMALOG 75 / 25™, HUMULIN 50 / 50™, HUMALIN 75 / 25™, HUMALIN L™, HUMALIN N™, HUMALIN®, HUMALIN R U-500™, HUMALIN U™, ILETIN IILENTE™, ILETIN II NPH™, ILETIN II REGULAR™ LANTUS™, NOVOLIN 70 / 30™, NOVILINN™, NOVILIN R™, NOVOLOG™, VELOSULIN BR™, and EXUBERA™. In another embodiment, the insulin analog may be lispro insulin, aspart insulin, glutathione insulin, admelog, NPH insulin, protamine zinc insulin, glargine insulin, detemir insulin, or degludec insulin, or their salts, hydrates, solvates, hydrated polymorphs, or cocrystals.

[0040] Another embodiment focuses on a method for preparing a water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, the method comprising the steps of: mixing the sugar and the pharmaceutical compound in at least 85% ethanol at a molar ratio of about 1 to about 12 moles of sugar per mole of pharmaceutical compound until dissolved, thereby forming a water-soluble complex, wherein the formation of the water-soluble complex is determined by nuclear magnetic resonance spectroscopy (NMR), and wherein the sugar is one or more of raspberry glycoside, neohesperidin A, dulcitin B, dodecyl-β-D-maltodextrin (DDM), or carabinin; wherein the mixing step is optionally carried out with a pharmaceutically acceptable acid; and drying the water-soluble complex and resolving the water-soluble complex in water, wherein the pharmaceutical compound is a peptide or small compound for lowering blood glucose and / or blood A1C in a subject, wherein the pharmaceutical compound is insulin, an insulin analog, a natural insulin variant, a GLP-1 receptor agonist, an incretin mimic, a GIP agonist, an amylin agonist, a glucagon agonist, or a salt thereof.

[0041] When the pharmaceutical compound used in the method for preparing the water-soluble complex is an insulin analog, it may be any one of insulin lispro, insulin aspart, insulin glutathione, admelog, NPH insulin, protamine zinc insulin, insulin glargine, insulin detemir, or insulin degludec. Alternatively, if the pharmaceutical compound is insulin or an insulin analog, it may be rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or ultra-long-acting insulin (e.g., insulin detemir / Levemir, insulin glargine, and insulin degludec / Tresib).

[0042] In another embodiment, when the pharmaceutical compound in the method for preparing the water-soluble complex is a GLP-1 receptor agonist, the GLP-1 receptor agonist is semaglutide, telposide, amiklipine, oxaliplatin, abiglutide, benaglutide, caglionetin, CagriSema, CT996, dapagliflozin, afenotinide, HM15211, lixisenatide, peptidoglycan, retaglutide, SCO-094, sovoglutide, WK2735, mascara, PEG-profenatide (PEX168), liraglutide, dulaglutide, ezenatide, or a salt thereof.

[0043] In another embodiment, when the pharmaceutical compound in the method for preparing the water-soluble complex is a GIP agonist, the GIP agonist is HM15211, rapaglutide, SCO-094, telpoglycinide, WK2735, ZP6590, or a salt thereof.

[0044] In another embodiment, when the pharmaceutical compound in the method for preparing the water-soluble complex is a glucagon agonist, said glucagon agonist is affinoside, HM15211, mascara, pevitide, sovorutide, or a salt thereof.

[0045] In another embodiment, when the pharmaceutical compound in the method for preparing the water-soluble complex is an amylin agonist, the amylin agonist is AZD6234, caglitinide, CagriSema, CT388, a long-acting amylin agonist, amiklipine, ZP8396, or a salt thereof.

[0046] The method may also include drying the water-soluble complex to form a solid. The dried solid can then be redissolved in a suitable liquid.

[0047] In some embodiments, the method for preparing the water-soluble complex may further require the presence of an added pharmaceutically acceptable acid in the mixing step (i.e., step 1) in the presence of a sufficient amount of pharmaceutically acceptable acid to solubilize and homogenize the reaction mixture. Pharmaceutically acceptable acids used in this method may include acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

[0048] This method can be used alone with a surfactant and solvent, or in the presence of an acid or buffer solution. The solvent used in this method can be a pure solvent, such as absolute ethanol, or a solvent mixture of ethanol, water, and methanol as suggested herein. Sugars, pharmaceutical compounds, and solvents can be placed in a container with the surfactant, and the pH can then be adjusted until a homogeneous solution is formed. Preferably, the homogeneous solution remains stable for at least 30 minutes, more preferably at least 2 hours, and even more preferably at least about 24 hours. An exemplary surfactant is a nonionic surfactant.

[0049] A method for preparing a water-soluble complex may involve mixing a non-nutritive sugar at a molar ratio of about 1 to about 12 moles per mole of the pharmaceutical compound. The sugar may be any of the DTG, DDG, or other non-nutritive sugars discussed herein, such as carbapenem and raspberry. Alternatively, the water-soluble complex prepared by this method may have a molar ratio of about 2 to about 10 moles of non-nutritive sugar per mole of the pharmaceutical compound (i.e., a drug:sugar molar ratio of about 1:2 to about 1:10), or a molar ratio of about 3 to about 5 moles of non-nutritive sugar per mole of the pharmaceutical compound (i.e., a drug:sugar molar ratio of about 1:3 to about 1:5). In another embodiment, the water-soluble complex formed by this method may contain a molar ratio of about 3 moles of sugar per mole of the pharmaceutical compound (a drug:sugar molar ratio of about 1:3) and an amount of any 0.1 between 1:1.0 and 1:12.0.

[0050] These and other embodiments will become apparent to those skilled in the art upon reading this specification. Brief description of the attached diagram

[0052] Figure 1 The NMR results of the water-soluble complex formed by carhariin (sugar) and lispro insulin (drug compound) are described.

[0053] Figure 2 NMR results for a water-soluble complex formed by carhariin (a sugar) and smegglutinin (a pharmaceutical compound) are described.

[0054] Detailed description

[0055] This paper describes a novel method for developing water-soluble complexes that enhance the formation of glucose and / or A1C regulating compounds, namely compounds that lower blood glucose and / or A1C levels in subjects with elevated blood glucose and / or A1C levels. A1C / glucose regulating compounds may include insulin, as well as glucagon-like peptide-1 (GLP-1) agonists and glucose-dependent islet-stimulating peptide (GIP) agonists. These compounds may have poor or insufficient water solubility, or be unsuitable for oral delivery, for example, due to unacceptable taste or consistency. The ability to fabricate complexes containing A1C / glucose regulating compounds has significant implications for many fields, including pharmacology and animal care. Complexes formed using the methods described herein can facilitate pharmacy formulation of subject-specific amounts of active compounds, as well as formulation of palatable pediatric or geriatric patient preparations.

[0056] In complexes of sugars and A1C-regulating compounds, the complex and / or the complex formed by the sugar compound increases the solubility of the compound in water compared to the compound alone (not in the complex). The complex also imparts a sweeter taste, rather than the bitter or pungent taste imparted by many salts; however, the addition of sugar to form the complex is not as a sweetener, but rather to form a complex with idebenone to enhance the water solubility of the complex form. Sweetness may be beneficial when administering the drug to children and elderly patients, but this is not for the purpose of non-nutritive sugars used to form the complex.

[0057] While the complex of non-nutritive sugars and drugs (i.e., A1C-modifying compounds) may be more palatable, it must be understood that the formation of the complex is not solely for masking the taste of the drug. Improving the palatability of the drug is a secondary benefit. The formation of water-soluble complexes by the methods described herein can result in improved drug properties in the complex form, such as improved water solubility. Furthermore, improved properties may include improved pharmacokinetic properties, improved pH and / or storage, and stability under high temperature or other conditions. Pharmacokinetic properties include absorption into the system, distribution within the system, metabolism of the complex in the system, and its elimination. Furthermore, based on the data and description herein, it should be understood that the water-soluble complexes formed by the methods described herein should not be considered mixtures. The method of dissolving the PSD (drug compound) and the listed non-nutritive sugars in the listed solvents or combinations of solvents may optionally be carried out in the presence of an acid / base / surfactant (e.g., a nonionic surfactant), followed by drying using the methods described herein. The dried complex is then dissolved in water (step 2), and optionally the solution is filtered and / or the complex is dried to remove water. The final water-soluble complex yields a new, more water-soluble drug in the form of a complex.

[0058] The water-soluble complex can then be mixed with other pharmaceutical excipients, stabilizers, fillers, flavoring agents, sweeteners, etc., as described herein. The composition is only in the form of a mixture after the addition of one or more of these other components. Unbound by theory, the complex formed by methods for forming a complex with the non-nutritive sugars and A1C-regulating compounds disclosed herein, optionally with surfactants in the complex as described herein, can involve host-guest chemistry, which is not possible when forming mixtures of different components. The solubility of the complex is independent of the addition of other pharmaceutical excipients, stabilizers, fillers, flavoring agents, sweeteners, etc. Among other pharmaceutically acceptable components, the composition of interest may also contain salts, such as NaCl, KCl, or citric acid, for stabilizing purposes.

[0059] Another benefit of this method and the products produced by it is the reduction in the amount of active pharmaceutical ingredient, as greater solubility leads to higher bioavailability. Another benefit of the method for preparing the claimed composition is the cost-effectiveness of achieving the desired patient outcomes with fewer active compounds and less resource utilization.

[0060] The complexation of a drug with DTG, DDG, or other non-nutritive sugars can be interpreted as a donor (sugar)-receptor (drug) interaction, such as host-guest chemistry between the drug and one or more sugars. In effect, this complexation intertwines poorly soluble drugs with soluble non-nutritive sugars, essentially enabling the drug to capture the water solubility of the non-nutritive sugar. See, for example, "Absorption and distribution of steviol glycosides in animal and human models." Stevia Technology On July 31, 2023, the following URL was retrieved: https: / / www.steviashantanu.com / single-post / 2015 / 11 / 18 / absorption-and-

[0061] Distribution of steviol glycosides in animal and human models. Without being limited to any particular theory, the enzymatic cleavage of glucose groups leads to the breakdown (e.g., decomposition) of the complex, thereby releasing the poorly soluble drug. This process is slow enough that the large amount of drug released at any given time can be absorbed.

[0062] However, while the combined sugar and drug may be more palatable as a complex, it must be understood that the formation of the complex is not solely for masking the taste of the drug. Improving the palatability of the drug is a secondary benefit. The formation of water-soluble complexes by the methods described herein results in improved drug properties in the complex form, such as improved water solubility, improved pharmacokinetic properties of the drug in the complex form, and / or improved stability under pH or certain conditions. Pharmacokinetic properties include absorption into the system, distribution within the system, metabolism of the complex in the system, and its elimination. Furthermore, based on the data and description herein, it should be understood that the formation of water-soluble complexes by the methods described herein is achieved through methods such as dissolving the listed sugars and drugs in the listed solvents or combinations thereof, optionally in the presence of an acid / base / surfactant (and / or poloxamer) surfactant, then drying using the methods described herein, dissolving the dried form in water and optionally filtering and / or drying; all of these methods result in the formation of new, more water-soluble drugs in the complex form. The water-soluble complex can then be further mixed with other pharmaceutical excipients, stabilizers, fillers, flavoring agents, sweeteners, etc., as described herein.

[0063] Not limited to any particular theory, the proposed water-soluble complexes can be generated through hydrogen bonding or through host-guest chemical formation, where two compounds are in the complex and one chemical compound has a cavity that can accommodate the "guest" compound. Surfactant-drug-nonnutritive sugar complexes can also involve hydrogen bonding. Water-soluble complexes can also be formed from surfactant and drug compounds. In inclusion complexes, the interaction between the host and guest involves only van der Waals bonds. In the sugar-compound form, aggregates and / or water-soluble complexes formed from nonnutritive sugars and / or surfactants and drug compounds (e.g., where the water-soluble complex can be surfactant and drug, surfactant and sugar, or surfactant, sugar, and drug) increase the solubility of the compound in water compared to the individual compounds. Such complexes also impart a sweeter taste, rather than the bitter or pungent taste imparted by many salts. Sweetness can be beneficial when administering drugs to children and elderly patients by contributing a sweeter and more palatable taste.

[0064] The anticipated water-soluble complex can also improve the amount of drug compound delivered (C). max Water-soluble complexes can obviously also prevent irritation from stomach acid. For certain compound drugs, and without being bound by theory, the dosage of the drug in the compound form may need to be reduced relative to the drug not in the compound form.

[0065] The complexation of a drug compound with nonnutritive sugars and / or surfactants (e.g., where the water-soluble complex can be a surfactant and a drug, a surfactant and a sugar, or a surfactant, a sugar, and a drug) can be interpreted as a donor (e.g., sugar or surfactant or both)-receptor (drug) interaction, such as the host-guest chemistry between the drug compound and nonnutritive sugars and / or surfactants (e.g., where the complex can be a surfactant and a drug, a surfactant and a sugar, or a surfactant, a sugar, and a drug) as listed herein. In effect, the complexation is an interweaving of the drug compound with soluble sugars, which essentially allows the drug compound to capture the water solubility of the sugar. Furthermore, after ingestion, this captured solubility may be retained in the upper gastrointestinal tract (GI).

[0066] definition

[0067] The following definitions provide guidance on the interpretation of terms, unless otherwise indicated in the context in which the term appears in other parts of this specification.

[0068] As used herein, the terms “optional” or “optionally” mean that an event or situation described below may or may not occur, and the description includes instances in which the event or situation occurs and instances in which it does not occur.

[0069] As used herein, the term "about," when used before a numerical specification, such as temperature, time, amount, concentration, etc., including ranges, indicates an approximate value that may vary (+) or (-) 15%, 10%, 5%, 1%, or any subrange and / or value in between. When referring to dosage, the term "about" means that the dosage may vary by + / - 10%. When referring to the amount of a modifying substance or composition (e.g., kg, L, or equivalent), the value of a physical property, or the value of a parameter of a method step in characterizing a method step (e.g., the temperature at which the method step is performed), the term "about" refers to numerical variations that may occur due to, for example, typical measurement, processing, and sampling methods involved in the preparation, characterization, and / or application of the substance or composition; unintentional errors in these methods; differences in the manufacture, source, or purity of the ingredients used to make or use the composition or in performing the method. In some embodiments, "about" may refer to a variation of ±0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, or 5.0 in appropriate units. In some implementations, “about” can refer to a change of ±1%, 2%, 3%, 4%, 5%, 10%, or 20%.

[0070] As used herein, the terms “comprising” or “comprises” are intended to mean that a composition or method includes the listed elements, but does not exclude other elements.

[0071] As used herein, the term "consistent primarily of" when used to define compositions and methods should mean excluding other elements that are of any significance to the stated purpose of improving the solubility of insulin or its analogues or GIP or GLP-1 agonists. Therefore, a composition consisting substantially of the elements defined herein, or a method consisting substantially of the steps defined herein, does not exclude other materials that do not substantially affect the essential and novel characteristics of the claimed subject matter.

[0072] As used herein, the term "composed of" should refer to the absence of any other ingredients or substantial method steps beyond trace amounts. Embodiments defined by each of these transitional terms are within the scope of this disclosure.

[0073] The molar ratio of sugar to drug compound in the formulation (wherein "drug compound" or "compound" is intended to refer to insulin, insulin homologs, GLP-1 agonists, and GIP agonists) can be from about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, and 9:1 to about 10:1 and any value in between, 0.1. 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 that range, 0.01. In one embodiment, a sugar to drug compound ratio of about 2.0 to about 1.0 molar ratio is used.

[0074] The term "pharmaceutically acceptable salt" refers to a salt (including internal salts, such as zwitterions) that has similar efficacy to the parent compound and is not biologically or otherwise undesirable (e.g., neither toxic nor harmful to the recipient). As used herein, the term "salt" means any of the following: acidic salts formed with inorganic and / or organic acids, and basic salts formed with inorganic and / or organic bases. However, the compositions / compounds described herein are sugar forms (sugar complexes) of one or more pharmaceutical compounds. Pharmaceutical compounds complexed with non-nutritive sugars can be either salt forms of the drug or the compound, or free forms of the compound. Salt forms of pharmaceutical compounds can allow the salt component to occupy binding sites on non-nutritive sugars; therefore, it may be important to use either salt or free forms to form water-soluble complexes if the compound lacks sufficient binding sites. Pharmaceutically acceptable salts are salts approved by the US FDA or the European Medicines Agency (EMA) for use in pharmaceuticals. The application of pharmaceutically acceptable salts used in the methods described herein is to improve the water solubility of sugars and water-insoluble drugs or drugs with limited solubility. Pharmaceutically acceptable acids include 1-hydroxy-2-naphtholic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetaminobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); decanoic acid; hexanoic acid; caprylic acid; carbonic acid; cinnamic acid; tartaric acid; citric acid; cyclamic acid. (acid); dodecyl sulfate; ethane-1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactobionic acid; gentian acid; glucoheponic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutamate; glycerophosphate; glycolic acid; hippuric acid; hydrobromic acid; hydrochloric acid; isobutyric acid; lactic acid (DL); lacturonic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; nitric acid; oleic acid; oxalic acid; palmitic acid; dihydroxynaphthalic acid; phosphoric acid; propionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanate; toluenesulfonic acid (p); and undecenoic acid. See, for example, PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts Weinheim / ZürichWiley-VCH / VHCA, 2002.

[0075] Examples of "bases" that include "pharmaceutically acceptable bases" include sodium hydroxide, zinc hydroxide, calcium carbonate, potassium hydroxide, lithium hydroxide, rubidium hydroxide, magnesium hydroxide, barium hydroxide, calcium hydroxide, strontium hydroxide, and potassium oxide. Other bases include trimethylamine, methylamine, aniline, and pyridine. Buffers can also be used in place 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).

[0076] The terms "compound," "drug-compound," and "drug" refer to "A1C-regulating compounds," such as insulin, insulin analogs (e.g., lispro insulin, aspart insulin, glutathione insulin, glargine insulin, detemir insulin, degludec insulin), GIP agonists, GLP-1 agonists (e.g., peptide mimics of GLP-1), and dual GIP / GLP-1 agonists. Such compounds are expected to lower blood glucose levels in subjects. The compound may or may not be poorly soluble in water. Exemplary compounds may include insulin, insulin analogs as listed herein, and GLP-1 agonists such as smegglutide, dulaglutide, and liraglutide. In some cases, a drug compound may be referred to as a "poorly soluble drug," "poorly soluble compound," or "inadequately soluble." A drug compound may be the free form of the compound or a pharmaceutically acceptable salt thereof. "Drug," "compound," or "drug compound" refers to both water-soluble and poorly water-soluble compounds. The compound may be an A1C and / or glucose-regulating compound that may not be considered water-soluble, thus impairing its commercial use. The pharmaceutical compounds used in the combination include "glucose-regulating compounds and / or compounds for the treatment of type 1 diabetes (TD1) or type 2 diabetes (TDI), obesity (weight loss), MASH (metabolic dysfunction-associated steatohepatitis), glycemic control, prediabetes, conditions characterized by impaired fasting glucose or impaired glucose tolerance (e.g., insulin resistance), α- and β-cell dysfunction, and conditions with suboptimal incretin effects."

[0077] The loss of commercial utility due to poor or inadequate solubility of drugs includes recognized insufficiency in water solubility, which can be demonstrated through attempts to improve solubility, including but not limited to the use of nanotechnology, prodrug administration, and delivery with non-aqueous solvents. The term "insoluble" is generally used in the art for compounds that are poorly or very poorly soluble (see, for example, Savjani et al., "Drug Solubility: Importance and Enhancement Techniques,"). ISRN Pharm(2012, doi:10.5402 / 2012 / 195727). Generally, a poorly soluble compound is considered "poorly soluble" in water at 20 °C when its solubility in the physiological pH range is less than about 1 mg / mL (see, for example, C. Moreton, "Poor Solubility – Wheredo we stand 25 years after the 'Rule of Five'?"). Amer. Pharm. Rev (2021). Drugs may also be inadequately soluble for commercial purposes; “inadequately soluble” refers to drugs with limited water solubility that, due to the formation of water-soluble complexes, such as those described herein, possess at least one improved pharmacokinetic property (e.g., C). max Time to reach C max (Stability, duration, etc.). Although not bound by theory, pharmaceutical compounds preferably have available hydrogen bonding sites to form such bonds with sugars and / or surfactants (e.g., where the complex can be a surfactant and drug, a surfactant and sugar, or a surfactant, sugar, and drug) and / or to form a complex with a sugar. The water insolubility (and limited solubility) of pharmaceutical compounds can be addressed by the complexation methods described herein. The oral bioavailability of a compound depends on several factors, including water solubility, drug-compound permeability, dissolution rate, first-pass metabolism, pre-systemic metabolism, and sensitivity to efflux mechanisms. The most common causes of low oral bioavailability are poor solubility and low permeability. Solubility also plays an important role in other dosage forms, such as parenteral formulations. Solubility is one of the important parameters for achieving the desired concentration of a pharmaceutical compound in systemic circulation to achieve the desired pharmacological response. Poorly water-soluble drugs often require high doses after oral administration to achieve therapeutic plasma concentrations. Water is the solvent of choice for liquid pharmaceutical formulations. Unfortunately, many drugs are weakly acidic or weakly basic, and therefore poorly water-soluble. More than 40% of NCEs (new chemical entities) developed in the pharmaceutical industry are practically insoluble in water. These poorly water-soluble drugs have slow absorption of the drug compound, leading to inadequate and variable bioavailability, as well as gastrointestinal mucosal toxicity. For orally administered drugs, solubility is the most important rate-limiting parameter in order to achieve the concentrations desired for a pharmacological response in systemic circulation (Savjani et al., 2012).

[0078] The term "nonionic surfactant" refers to pharmaceutically acceptable poloxamer surfactants or polysorbate surfactants as described herein. The ratio of "drug" to nonionic surfactant can be 1:10, 1:5, and 1:0.5, as well as any 0.1 value of surfactant between about 0.5 and 10.0.

[0079] The solubility of the drug compounds discussed in this article can vary. Some drugs may be soluble only in DMSO or DMF, or have limited solubility in ethanol, methanol, or acetonitrile. For example, the solubility of some compounds can be found at toku-e.com / solubility-data-resource / . Solubility ranging from soluble to very soluble is characterized by a range from no more than 30 parts solvent per part solute to less than 1 part solvent per part solute. Poor solubility and limited solubility include the ranges of “sparingly soluble,” “slightly soluble,” “very slightly soluble,” and “practically insoluble,” as shown below (Savjani et al., 2012):

[0080] The terms "compound," "drug compound," and "drug" refer to substances including "GLP-1 agonist," "GIP agonist," incretin, dual GLP-1 / GIP agonists, amylin agonists / analytes, dual amylin / calcitonin receptor agonists, dual GLP-1 / amylin agonists, and GLP-1+GIP+glucagon agonists (triple agonists). Exemplary compounds are listed below.

[0081] Table 1

[0082] For more information, see Tran et al., “Overview of Glucagon-Like Peptide-1 Receptor agonists for the Treatment of Patients with Type 2 Diabetes,” Am. Health Drug Benefits10(4): 178-188 (2017) and “Long Acting GLP-1 Receptor Agonist Drugs Lists and Overview” are available at www.biochempeg.com / article / 226.html, and “Exploring FDA-approved GLP-1 receptor agonists” is available at pharmanewsintel.com / features / exploring-fda-approved-glp-1-receptor-agonists.

[0083] In embodiments of the method for dissolving drug compounds and sugars described herein, the pH of the compound, sugar, and solute can be adjusted to approximately 2.0 to approximately 12.0, depending on the dissolution requirements. Depending on the solubilization needs, the pH can be adjusted to any value between 2.0 and 12.0, with a margin of 0.1.

[0084] In embodiments of the method for dissolving compounds or sugars described herein, the temperature of the compounds, sugars, and solutes can be from about 15 °C to about 60 °C, typically and preferably from about 5 °C to about 10 °C away from room temperature. Exemplary temperature ranges are from about 20 °C to about 30 °C.

[0085] A "pharmaceutically acceptable composition" is a composition comprising a hydrogen-bonded and / or sugar-A1C modulating compound complex and one or more carriers, excipients (e.g., gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, and PEG), stabilizers (e.g., glycine, vitamin E, carboxymethyl cellulose, sodium lauryl sulfate), thickeners, flavorings, colorings, and another sweetener, which form a mixture with a water-soluble complex formed by the methods described herein, but are not essential for the solubility of the pharmaceutical compound. The composition may be in solid or liquid form. The pharmaceutical composition may also comprise an A1C modulating compound with a surfactant or an A1C modulating compound with a surfactant and a non-nutritive sugar. Such excipients, carriers, stabilizers, thickeners, flavorings, and / or colorings should be compatible with the complex. Other suitable pharmaceutically acceptable excipients include water, saline, glucose, glycerol, and ethanol, or combinations thereof. Intravenous media for delivering the water-soluble complex include fluids and nutritional supplements, electrolyte supplements, such as Ringer's glucose-based supplements, etc. Aqueous carriers for liquid formulations containing water-soluble complexes include water, alcohol / water solutions, emulsions, or suspensions, including saline or buffer media. Pharmaceutically acceptable carriers for parenteral administration include sterile, aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous parenteral media for delivering water-soluble complexes include sodium chloride solution, Ringer's glucose, glucose and sodium chloride, lactated Ringer's solution, or fixed oil.

[0086] For water-soluble drug compounds, the method described herein for combining such water-soluble drugs with non-nutritive sugars involves creating a drug compound-sugar complex that can be continuously released when orally administered to the gastrointestinal tract of a subject receiving the complex.

[0087] The terms “compound,” “pharmaceutical compound,” or “poorly soluble drug” also include insulin, insulin variants, or insulin analogs, wherein said insulin, insulin variants, or insulin analogs may or may not be poorly soluble or insoluble (e.g., poorly soluble drug, PSD). The terms “compound,” “pharmaceutical compound,” or “poorly soluble drug” also refer to pharmaceutical compounds including GLP-1 agonists, amylin agonists, glucagon agonists, GIP agonists, and more than one of these agonist activities. While not bound by theory, pharmaceutical compounds preferably have available hydrogen bond sites to form such bonds with non-nutritive sugars and / or surfactants (e.g., where the complex can be a surfactant and a drug, a surfactant and a sugar, or a surfactant, a sugar, and a drug), and the pharmaceutical compounds form complexes. For the compounds and methods described herein, the pharmaceutical compound is insulin or an insulin analog, such as lispro insulin (Humalog®). The pharmaceutical compound is a compound that can be dissolved in amounts not exceeding about 100 mg per milliliter, and possibly less than 50 mg per milliliter. As used herein, a “water-soluble complex” includes complexes comprising a non-nutritive sugar and a pharmaceutical compound, a surfactant and a pharmaceutical compound, and a surfactant / non-nutritive sugar / pharmaceutical compound. The terms “sugar-compound,” “sugar-pharmaceutical compound,” and “sugar-pharmaceutical” are equivalent terms used to describe complexes between non-nutritive sugars and pharmaceutical compounds. The resulting water-soluble complex may be used to treat the conditions described herein or may modulate one or more of a subject’s GIP, GLP-1, amylin, glucagon, A1C levels, or glucose levels. When not complexed with non-nutritive sugars such as those described herein, the pharmaceutical compound may or may not be a poorly soluble drug / compound; the pharmaceutical compound has available hydrogen bonding sites to form such bonds with non-nutritive sugars and / or surfactants (e.g., where the complex may be a surfactant and a drug, a surfactant and a sugar, or a surfactant, a sugar, and a drug), forming a water-soluble complex. As used herein, the terms “complex” and “aggregate” and “inclusion complex” are used interchangeably and are intended to be equivalent to, including, the descriptions provided herein and those claimed in the priority claims of this application, including but not limited to, the terms “complex containing,” “aggregate,” and “complex.” Each of these terms refers to a stable product formed between a sugar and a compound as described herein. The compound may be a pharmaceutical compound that requires improved water solubility, an A1C modulating compound, or any other compound. In the general formula provided herein, “DTG” refers to a diterpenoid glycoside, including DDG and other non-nutritive sugars described herein, and pharmaceutical compounds as “medicines” as shown in the following formula:

[0088] A water-soluble complex is a water-soluble complex of formula (I) prepared by the methods described herein, which can be prepared and isolated, and whose structure and properties remain or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject), sufficient to allow the pharmaceutical compound in the water-soluble complex to be used for the purposes described herein (e.g., therapeutic administration to a subject). Another feature that can be conferred by methods that improve the water solubility of the compound is that the storage stability of the water-soluble complex can be higher than that of the pharmaceutical compound when it is not in complex form. By way of example only, a complex is considered stable if the water-soluble complex of any of the above-described complexes remains intact in water at pH 8.5 for at least 2 hours, and / or if it remains intact in water at pH 4 for at least 2 hours. Alternatively, or additionally, a water-soluble complex is considered stable if it remains intact at 30 °C for at least 90 days when dried into a powder. Thus, in a preferred embodiment, a complex is considered a stable complex when it meets any or all of these stability tests. Alternatively, the water-soluble complex formed by the method described herein forms a dry complex that does not require refrigeration and is stable at room temperature for at least 24 hours. Alternatively, the water-soluble complex formed by the method described herein exhibits at least two (2), three (3), four (4), or (5) times increased water solubility at 20°C compared to the water solubility of the drug compound when not combined with sugars and / or surfactants (e.g., where the complex can be a surfactant and a drug, a surfactant and a sugar, or a surfactant, a sugar, and a drug). Alternatively, the maximum amount of sugar provided by the water-soluble complex in a daily unit dose of the water-soluble sugar-A1C-modified complex does not exceed about 280 mg. Alternatively, a drug with limited water solubility may have at least one improved pharmacokinetic property in the water-soluble complex (e.g., C... max Reaching C max (Time, stability, duration, etc.). A "stable" water-soluble complex (i.e., [DTG]) p The drug can be prepared by the methods described herein, and the complex can be prepared and isolated, and its structure and properties remain or can remain substantially unchanged over a period of time, sufficient to enable the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0089] The term "insulin" or "insulin analogue" refers to a pharmaceutical compound that is insulin, a naturally occurring insulin variant, or an insulin analogue. Insulin analogues are recombinant proteins based on the amino acid sequence and structure of insulin, such as human insulin, but with selected amino acid substitutions, deletions, or additions. Insulin analogues achieve glucose control but have altered pharmacokinetics, such as altered timing and duration of insulin action. A non-limiting example of an insulin analogue is lispro insulin; this insulin analogue has two mutations in its B-chain: the amino acid proline at position B28 is replaced by lysine, and the amino acid lysine at position B29 is replaced by proline. Lispro insulin has a faster blood glucose-lowering effect than natural insulin. As used herein, insulin / insulin analogues include, but are not limited to, rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, ultra-long-acting insulin, and premixed insulin. The onset, peak time, and duration of insulin action vary. Onset refers to how quickly insulin lowers a subject's blood glucose level. Peak time refers to the time it takes for insulin to reach its maximum strength. Duration refers to the duration of insulin's blood glucose-lowering effect. The following is an overview of the different types of insulin (data from www.cdc.gov / diabetes / basics / type-1-types-of-insulin.html). Human insulin is marketed under various brand names, including Actraphane, Actrapid, Humulin, Humulin N, Humulin R, Insulatord, Entuzity, Novolin, Novolin N, Novolin R, Insuman, and Myxredlin. Human insulin is available in two forms, a regular or short-acting form, or an intermediate-acting form called neutral protamine Hagedorn (NPH) insulin. The table below lists the forms of human insulin and insulin analogs. Insulin and insulin analogs can be approved for use in type 1 and / or type 2 diabetes.

[0090] Table 2

[0091] Exemplary insulins and insulin analogues include, but are not limited to, insulin lispro (e.g., Humalog®), insulin aspart (e.g., NovoLog™), bovine insulin, insulin degludec (e.g., Tresiba®), and insulin detemir® (e.g., Levemir® having). des-B30), glargine insulin (e.g., Lantus™), glutathione insulin (e.g., ApidraA®), Pork insulin (e.g., Iletin® II), regular insulin (e.g., Humulin® R), porcine insulin (e.g., Vesullin), and protamine zinc insulin (e.g., Novolin® N). Other examples of commercially available products include HUMALOG™, HUMALOG 50 / 50™, HUMALOG 75 / 25™, HUMULIN 50 / 50™, HUMALIN 75 / 25™, HUMALIN L™, HUMALIN N™, HUMALIN®, HUMALIN R U-500™, HUMALIN U™, ILETIN II LENTE™, ILETINII NPH™, ILETIN II REGULAR™ LANTUS™, NOVOLIN 70 / 30™, NOVILIN N™, NOVILIN R™, NOVOLOG™, VELOSULIN BR™, and EXUBERA™. See, for example, Jarosinski et al., “New Horizons: Next-Generation Insulin Analogues: Structural Principles and Clinical Goals,” J. Clin. Endocrin. & Metab. 107(4): 909-28 (2022). Also of interest are insulin analogs that are premixed after being combined with glucose. “Premixed insulin” combines two types of insulin to control blood glucose levels throughout the day. For example, it may include rapid-acting insulin and long-acting insulin. This insulin may also be suitable for cats and dogs with elevated blood glucose levels.

[0092] Methods for preparing water-soluble complexes containing pharmaceutical compounds involve dissolving the compound in ethanol in the presence of DTG or other non-nutritive sugars, followed by drying the liquid from the composition (e.g., lyophilization or freeze-drying). Optionally, the dissolution step may also involve the use of one or more pharmaceutically acceptable acids. Lyophilization may require pre-freezing of the complex, followed by preliminary and secondary drying steps to obtain a dried water-soluble complex, typically in powder form. The dried form from the first solubilization step must then be resoluble in water. Subsequently, the water-soluble complex can be dried and formulated as desired. For example, the water-soluble complex formed by this method can then be formulated into a solid form for oral, sublingual, and / or oral administration, such as pills, capsules, pouches, chewable tablets (e.g., gummies), tablets, lozenges, and / or soft gels. Water-soluble A1C-modified complexes (e.g., hydrogen-bonded and / or inclusion complexes of sugar-drugs) can also or alternatively be formulated for topical application, such as suppositories, lotions, gels, and / or ointments. Water-soluble A1C modulating complexes (hydrogen-bonded and / or inclusion complexes of nonnutritive sugars and pharmaceutical compounds, and optionally nonionic surfactants) can also be formulated into inhalable powders. For example, insulin and insulin analogs can be administered via syringes, insulin pens, insulin pumps, or inhalers. Alternatively, water-soluble complexes can be formulated into injectable liquids for administration to subjects via subcutaneous (SC), intravenous (IV), intraperitoneal (IP), and intramuscular (IM) routes. Or, lyophilized water-soluble complexes can be formulated into liquid formulations for administration, such as as an inhalation mist or nebulized by a patient. For example, insulin and insulin analogs can be administered via syringes, insulin pens, insulin pumps, or inhalers (Mohanty et al., “Inhaled Insulin – Current Direction of Insulin Research,”). J. Clin. Diagn. Res11(4): doi: 10.7860 / JCDR / 2017 / 23626.9732, 2017. Other peptides may also be administered in this formulation or using this device. In the case of non-human subjects, the lyophilized water-soluble complex may be administered to non-human subjects as a powder or liquid formulation. Alternatively, the lyophilized water-soluble complex may be formulated as a food additive or added as an additive to animal feed for the treatment of diabetic animals. Insulin analogs suitable for dogs and cats may be used as pharmaceutical compounds, for example. The pharmaceutical compound may be wholly or partially soluble in 95% ethanol, 50% ethanol or higher concentrations of aqueous ethanol (e.g., 50%, 55%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94% and 95% spectrophotometric grade ethanol) or in the presence of non-nutritive sugars in a combination of ethanol and another solvent. Preferably, the pharmaceutical compound and sugar, optionally having a pharmaceutically acceptable acid, are dissolved in at least about 85% ethanol. Optionally, the water-soluble complex remains soluble without forming a precipitate for at least 24 hours after its formation.

[0093] If desired, polyethylene glycol (PEG) can optionally be added to liquid and powder formulations to further improve bioavailability. Typically, it is 2,000-6,000 Daltons, 3,000-4,500, or 3,200-3,700 Daltons, and other pharmaceutically acceptable molecular weights used when formulating PEG with chemical compounds. Common commercially available forms of PEG have molecular weights of 3,350, 4,000, and 6,000 Daltons. For example, PEG products can be polydisperse or monodisperse. If polydisperse, the molecular weight describes the weight-average molecular weight of the product. Depending on whether the product is in powder or liquid form, the weight ratio of PEG to the compound can be 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1. In one embodiment, the weight ratio is about 8:1. However, PEG does not contribute to conferring water solubility to the pharmaceutical compound.

[0094] For administration, the powder form can be reconstituted at the place of manufacture, at the dispensing pharmacy, or by the patient in a liquid medium. The liquid medium can be water, a buffered aqueous solution, a syrup, or an aqueous beverage, such as an energy drink or an electrolyte-rich beverage. For example, a water-soluble complex with improved solubility for the drug compound can be reconstituted in sterile saline or another sterile liquid carrier for administration to the subject via subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravenous (iv), local, or oral routes (oral administration into the gastrointestinal tract or sublingual or oral administration). Water-soluble complexes can also be formulated for delivery via subcutaneous or intramuscular injection.

[0095] Suitable ingredients for formulating tablets or pills or other solid oral forms of water-soluble complexes may include any or all of the following, such as corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, and hydroxypropyl methylcellulose. Other compositions incorporating the hydrogen-bonded and / or inclusion complex of the A1C-regulating compound may include a mixture of formulators, oral stool softeners, oral stimulants, and / or rectal suppositories.

[0096] Although the dissolution rate of water-soluble complexes is slow enough to allow drug compounds to enter the small intestine without precipitation in the stomach, other methods for prolonging drug compound release are known, such as enteric-coated tablets, coating the complex with a slowly dissolving polymer (the polymer can be selected according to the desired length and / or thickness to modify the release rate of the drug compound), encapsulating the water-soluble complex in gel capsules, encapsulating the water-soluble complex in an insoluble matrix (e.g., Slow-K or Imdur Durules), encapsulating the water-soluble complex in an erosive matrix (e.g., MST Continus, Phyllocontin Continus), and / or encapsulating the water-soluble complex in a semi-permeable membrane. See, for example, “Pharmaceutical Issues when Crushing, Opening or Splitting Oral Dosage Forms,” Royal Pharmaceutical Society, June 2011. Other oral dosage forms that improve release include “extended-release drug products,” where the dosage form of the water-soluble complex allows for a dose frequency that is at least twice as low as that provided in a non-extended-release form. Examples of extended-release dosage forms include controlled-release, sustained-release, and / or long-acting drug products. Another modified-release oral dosage form is the delayed-release drug product. In delayed-release forms, the water-soluble complex dosage form releases one or more discrete portions of the water-soluble complex over a specified period of time instead of rapidly after administration. Enteric-coated dosage forms are common delayed-release products (e.g., enteric-coated aspirin and other NSAID products). Another modified-release oral dosage form of the water-soluble complex of interest is the targeted-release drug product. This is a water-soluble complex dosage form that releases the water-soluble complex at and / or near the intended site of physiological action. Another modified-release oral dosage form of the water-soluble complex is the orally disintegrating tablet (ODT) or equivalent. ODTs have been developed to rapidly disintegrate in saliva after oral administration. The water-soluble complex in ODT form can be used without the addition of water. The water-soluble complex is dispersed in saliva and is swallowed with little or no water.

[0097] The term "delayed release" refers to the fact that the water-soluble complex is not released immediately, but rather slowly or at a later time after administration, such as 1 hour or 8 hours later. Improvements in delayed release can be achieved by using methods such as enteric-coated capsules. Alternatively, release can be achieved through subcutaneous injection into the subject. The water-soluble complexes described herein can be further formulated into targeted release forms.

[0098] By using powder or liquid formulations, it is easier to dispense appropriate doses of A1C-modifying compounds, thereby reducing errors, variability, and waste arising from variations in pill-fractionation techniques. Another benefit achieved through this method and the products produced by it is the reduced amount of active A1C-modifying compounds, as greater solubility leads to higher bioavailability. This method offers a cost-effectiveness by requiring less active compound and fewer resources, while still achieving the desired patient outcomes.

[0099] Any components can be packaged in the kit, individually in a single container, or mixed together. End users can reconstitute the components using the included diluent or a diluent of choice. In addition to individual or mixed components, the kit may also include instructions for use, mixing and / or application equipment, storage containers, etc. The kit may also be in the form of a prepared injectable, whether for single or multiple use, with or without instructions or means of obtaining instructions such as a QR code. The kit may be in the form of a single-use or multiple-use injection pen.

[0100] A "pharmaceutically acceptable composition" refers to one or more compositions comprising a water-soluble complex and a carrier, excipients (e.g., gelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch, sucrose, and PEG), stabilizers (e.g., glycine, vitamin E, carboxymethyl cellulose, sodium lauryl sulfate), thickeners, and additional sweeteners. The composition may be in solid or liquid form.

[0101] The term "improved solubility" refers to an improvement in the solubility of the compound in water, an improvement that does not exist when combined with a sugar as described herein. The solute used to dissolve the compound and sugar can be 80% methanol, 95% (ACS grade) methanol, anhydrous methanol, or methanol of higher concentrations, as well as combinations of methanol and ethanol or methanol and water. Combinations or combinations containing hexane may also be used. After dissolving the sugar and compound in ethanol or an aqueous ethanol solution, the ethanol is evaporated, for example, under a high rotating vacuum. The dissolved sugar and compound can be dissolved in any of the said solvents and then dried as described herein. The powder obtained from the evaporation step can then be redissolved (in water). As described above, the improvement in water solubility of the pharmaceutical compound in its complex form is measured at approximately 20 °C and compared with that in its non-complex form.

[0102] The terms "water-soluble complex" and "water-soluble sugar-drug complex" refer to a complex comprising a sugar (e.g., raspberry glycoside, stevia, dulcitin B, carhariin, n-dodecyl-β-D-maltodextrin, or neohesperidin A, or other sugars indicated herein) and a pharmaceutical compound, such as insulin or an insulin analogue or other A1C-regulating compound as described herein, which is formed by dissolving in 95% ethanol, optionally together with the pharmaceutically acceptable acid or base, optionally further dissolved in the presence of the pharmaceutically acceptable acid. The water-soluble complex may also contain a surfactant or may use a surfactant instead of the non-nutritive sugar. An exemplary surfactant is a nonionic surfactant. As used herein, the term "complex" means to include a compound, wherein a compound may also include multiple compounds.

[0103] The terms "animal" or "subject" can refer to both humans and domestic animals (e.g., cats and dogs) with elevated A1C or glucose levels. Subjects may be those treating obesity (weight loss), type 2 diabetes (TD2), MASH, glycemic control, prediabetes, conditions characterized by impaired fasting glucose or impaired glucose tolerance (e.g., insulin resistance), alpha and beta cell dysfunction, and / or conditions with suboptimal incretin effects. Subjects may also be those with type 2 diabetes. Prediabetes in human subjects is typically defined as falling within the 5.7-6.4% range. Therefore, subjects' A1C levels should generally be reduced to less than 7% (King et al., "Glucagon-Like Peptide 1 Receptor Agonists Have the Potential to Revolutionize the Attainment of Target A1C Levels in Type 2 Diabetes – So Why is Their Uptake So Low"). Clin. Diabetes 41(2): 226-38 (2023). The incretin effect describes the phenomenon that oral glucose induces a higher insulin secretion response than intravenous glucose (see, for example, Nauck et al., “The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions”). Lancet Diabetes Endocrinol4(6): 525-36 (2016). Cats and dogs also frequently suffer from diabetes and can be treated with adjunctive therapy using animal-appropriate insulin and other forms of medication.

[0104] The term "treating" or "treatment" refers to treating a subject with elevated levels of glucose and / or blood glucose by administering one or more compositions comprising a complex generated using the methods described herein. The compositions described herein can also be used to treat obesity (weight loss), type 1 diabetes (TD1), type 2 diabetes (TD2), MASH, glycemic control, prediabetes, conditions characterized by impaired fasting glucose or impaired glucose tolerance (e.g., insulin resistance), alpha and beta cell dysfunction, and suboptimal incretin effects. Subjects may be individuals or domestic animals, such as dogs or cats, with one or more similar conditions.

[0105] The molar ratio of the drug compound to the sugar is used as described herein. The range of the molar ratio of the drug compound to the molar ratio of the sugar is 1:1 to 1:12, 1:1 to 1:10, or 1:1 to 1:5. The “molar ratio” of sugar to drug compound listed herein can be 1.0 to 0.001 or 10.00 to 0.1 and any value of 0.01 between those two ranges. The “molar ratio” of sugar to drug compound in the formulation can be about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or about 10:1 and at most about 20:1, and any value of 0.1 between them. Alternatively, the ratio of sugar to drug compound can be about 1.00:1.00 to about 5.00:1.00 and any value of 0.01 within that range. In one embodiment, a sugar with an A1C regulating compound is used in a molar ratio of about 2.0 to about 1.0.

[0106] The term "daily unit dose" refers to the total amount of the drug compound administered to the subject daily, whether in a single or multiple administrations, and when used in a single administration, whether in one or more pills, capsules, tablets, or other formulations. The dose of a formulation containing the compound (e.g., a water-soluble complex) may contain an amount not exceeding the generally recognized safe (GRAS) level of any component in the formulation. For example, in the case of stevia sugar being used as a DTG, the dose may provide no more than about 10 mg / kg of stevia sugar, as exceeding this dose for an average 70 kg male would result in a single administration of a 700 mg dose of sugar. In another embodiment, the dose may provide the subject with no more than 5.0 mg / kg of stevia sugar. At amounts of 2.0 mg / kg, 3.0 mg / kg, 4.0 mg / kg, and 6.0 mg / kg in each dose are also of interest.

[0107] The method described herein involves dissolving a pharmaceutical compound in ethanol (or another listed solvent or combination of solvents) in the presence of a specified sugar, and then drying or evaporating the solvent from the composition (e.g., freeze-drying or lyophilization, or other means of evaporating ethanol or other solvents from the mixture) (step 1). Evaporation can be performed using various steps, including pre-freezing of the complex followed by primary and secondary drying steps. If lyophilization is used, conventional lyophilization adjuvants can be used in conjunction with the complex in solution. For step 2, the dried complex is then dissolved in water, and may be evaporated again if necessary. When the complex is dissolved in water in step 2, it may be further filtered to remove any particles. The water-soluble complex may be dried after dissolution in water or formulated into pellets or any other form described herein.

[0108] The water-soluble complex prepared by the disclosed method can be mixed with a pharmaceutically acceptable carrier formulation. "Pharmaceutically acceptable carriers" for parenteral administration include sterile, aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous carriers for liquid formulations containing water-soluble complexes include water, alcohol / water solutions, emulsions, or suspensions, including saline or buffer media. Parenteral media for delivering water-soluble complexes include sodium chloride solution, Ringer's glucose, glucose and sodium chloride, lactated Ringer's solution, or non-volatile oils.

[0109] Water-soluble complexes can be mixed with other pharmaceutically acceptable excipients that are compatible with the active ingredient in the drug. Suitable "pharmaceutically acceptable excipients" include water, saline, glucose, glycerol, and ethanol, or combinations thereof. Intravenous media for delivering water-soluble complexes include fluids and nutritional supplements, electrolyte supplements such as Ringer's glucose-based supplements, etc.

[0110] The water-soluble complex may optionally include preservatives and / or additives. Preservatives and additives of interest used with the water-soluble complex may include antimicrobial agents, antioxidants, chelating agents, inert gases, etc. After the complex is formed, the preservatives and / or additives are mixed with the water-soluble complex (e.g., by stirring).

[0111] Water-soluble complexes can be formulated into solid forms for oral, sublingual, or oral administration, such as pills, capsules, sachets, chewable tablets, tablets, lozenges, or soft gels. They can also be formulated as powders, orally disintegrating tablets, sublingual drops, sugar-free lollipops, sugar-free chewing gum, tinctures, capsules, films, sugar-free lozenges, chewable pills or gummies, pastes, or effervescent powders or tablets. Alternatively, the water-soluble complex can be used to prepare formulations for parenteral administration and can be administered intradermally, subcutaneously, intramuscularly, intraperitoneally, topically, or intravenously.

[0112] The oral formulation of this complex can be further modified depending on the animal to which the formulation is administered. As solubility increases, a dose reduction can generally be achieved in animals treated with the complex. Additional modifications to the final formulation containing the complex may include flavoring agents. The amount of the water-soluble complex to be administered is equivalent to or less of the amount of the active pharmaceutical compound if administered in a non-complex form. The amount administered is based on the subject's mg / kg body weight receiving the active pharmaceutical compound, based on or less than the amount of the previously approved non-complex form of the pharmaceutical compound. For example, for subjects, the oral formulation for carnivorous animals may be meat-flavored, while for vegetarian subjects and vegans, the composition may be fruit-flavored (such as apple or pear) or grass-flavored.

[0113] The complexes discussed herein can be prepared and formulated into single-use or multi-use syringes or pens. The syringes and pens can be pre-loaded. Pre-loaded syringes and pens can be distributed as kits with new needles and pre-set dosages; such pre-loaded syringes and pens can contain multiple doses in a single pre-filled syringe.

[0114] Also of interest are kits with pre-filled syringes, pens, or devices for administering the complex to subjects. The kit may include a water-soluble complex, an apparatus for mixing the water-soluble complex into a delivery agent (e.g., saline, water, lotion, gel, etc.), and a delivery device. For subjects who require it, the amount of water-soluble complex that can be mixed may be at the mg / kg level. Instructions for use may also be included in the kit.

[0115] The dissolution method in the first solvent step or water step (second step) may optionally include one or more acids or bases to further improve the solubility and / or stability of the water-soluble complex formed by the method. Preferably, the acid or base is a pharmaceutically acceptable acid or base for use with a drug. The acid or base may be added until the drug compound and sugar are dissolved.

[0116] For the first step, in the presence of sugar, the pharmaceutical compound can be completely or partially soluble in 95% ethanol, anhydrous ethanol, or an aqueous solution of 50% or more ethanol (e.g., 50%, 55%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, and 95% spectrophotometric grade ethanol and anhydrous ethanol). The pharmaceuticals and chemicals of interest include those that are insoluble, have limited solubility, and are soluble in water. The compound or pharmaceutical compound can be any free form of the compound or its salts, hydrates, solvates, hydrate polymorphs, eutectics, or salts of a specified free form of the pharmaceutical compound. The pharmaceutical compound and sugar are dissolved in at least about 85% ethanol, and optionally in the presence of an acid or base. In another embodiment, methanol can be added to ethanol, the pharmaceutical compound, the sugar, and optionally an acid / base, to further solubilize and form a complex. When using the listed sugars to form a complex, using a non-salt form of the compound may be more useful, as this provides more hydrogen pairing sites for sugar binding. Optionally, the water-soluble complex remains soluble without precipitation for at least 24 hours after formation. Alternatively, the solvent can be a co-solvent, such as a binary or ternary (or higher) mixture of solvents. For example, the co-solvent can be about 50% ethanol, with the remainder being a buffer solution or water, or different or additional solvents can be used in combination with water or a buffered aqueous solution. Generally, a ratio of ethanol to methanol as low as about 1:0.00005 (e.g., 95% or higher methanol) can improve solubility compared to using ethanol alone. Therefore, an ethanol to methanol ratio of 1:1 to 1:0.00001 (and all 0.00001 values ​​within this range) is expected. In some embodiments, methanol can be used instead of ethanol, making the methanol to ethanol ratio the opposite of the above ratios (e.g., 1:1 methanol to ethanol to 1:0.00001 methanol to ethanol, including all intermediate values). A combination of ethanol, methanol, and isopropanol can also be used.

[0117] Other pharmaceutically acceptable solvents that can be used alone or in combination to form water-soluble complexes include acetone, acetonitrile, anisole (methoxybenzene), benzene, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, carbon tetrachloride (tetrachloromethane), cumene, cyclohexane, 1,2-dichloroethane, 1,1-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane, ethanol, 2-ethoxyethanol, ethyl acetate, 2-ethoxy... The solvent may be ethanol, ethyl acetate, ethylene glycol, diethyl ether, ethyl formate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, 2-methoxyethanol, methyl acetate, 3-methyl-1-butanol (isoamyl alcohol), methyl butyl ketone, methyl cyclohexane, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, N-methylpyrrolidone, nitromethane, pentane, 1-pentanol, 2-propanol, propyl acetate, pyridine, sulfolane, tetrahydrofuran, tetrahydronaphthalene, toluene, 1,1,1-trichloroethane, 1,1,2-trichloroethylene, triethylamine, and xylene. In another embodiment, the solvent or solvent combination may be water, ethanol, DSMO, DMF, methanol, acetone, ethyl acetate, hexane, heptane, dichloromethane, tetrahydrofuran, acetonitrile, or toluene. Organic solvents of interest, alone or in combination, used in step 1 include hexane, p-xylene, toluene, diethyl ether, methyl tert-butyl ether (MTBE), diethylamine, dioxane, chlorobenzene, tetrahydrofuran, o-dichlorobenzene (ODCB), ethyl acetate, dimethoxyethane, pyridine, dichloromethane, HMPT, 1,2-dichloroethane, DMPU, acetone, dimethylformamide, tert-butanol, sulfolane, dimethyl sulfoxide, acetonitrile, nitromethane, 2-propanol, benzyl alcohol, ethanol, methanol, ethylene glycol, trifluoroethanol, hexafluoroisopropanol, and water. Water is preferably deionized water, distilled water, or a combination of deionized and distilled water. Non-nutritive sugars and PSDs (pharmaceutical compounds) should be dissolved in the solvent or combination of solvents used in this method. Preferred solvents include ethanol, methanol, chloroform, hexane, and their aqueous solutions. FDA-approved solvents were provided in June 2017. Q3C – Tables and List Guidance for IndustryThe FDA-approved solvents may be one or more of acetonitrile, chlorobenzene, cyclohexane, cumene, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane, N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, 2-ethoxyethanol, formamide, hexane, methanol, 2-methoxyethanol, methyl butyl ketone, methyl cyclohexane, methyl isobutyl ketone, N-methylpyrrolidone, nitromethane, pyridine, sulfolane, tetrahydrofuran, tetrahydronaphthalene, toluene, 1,1,2-trichloroethylene, and xylene, within the FDA's permitted limits. Another FDA list of solvents for step 1 includes one or more of acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, dimethyl sulfoxide, ethanol, ethyl acetate, diethyl ether, ethyl formate, heptane, isobutyl acetate, isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, 1-propanol, 2-propanol, propyl acetate, and triethylamine.

[0118] In some cases, the method for preparing water-soluble complexes may also include a surfactant in the solvent step (step 1) or water step (step 2) of the method described herein. Preferably, a surfactant is used in step 1. The surfactant may be a nonionic surfactant. The surfactant may also be used in combination with an acid or base in solution. The nonionic surfactant may be a polysorbate surfactant (PSS) and / or a poloxamer surfactant (“PXS”). PXS is a poloxamer surfactant, which is a class of nonionic amphiphilic triblock linear copolymers consisting of a central hydrophobic chain of a nonpolar block of poly(propylene oxide) (PPO) and two hydrophilic chains flanking a polar block of polyethylene oxide (PEO). Poloxamer surfactants with different molecular weights and PPO / PEO ratios can be obtained. The PXS surfactant is commercially available, such as Kolliphor® P (BASF, Florham Park, NJ), Pluronic® (BASF, Florham Park, NJ), Lutrol® (BASF SE, Ludwigshafen, Germany), and Synperonic™ PE (CRODA International PLC, East Yorkshire, United Kingdom). The PXS surfactant is obtained in liquid, flake, and paste physical forms. In one embodiment, PXS is a flake solid. Polysorbate surfactants (“PSS”) are derived from ethoxylated dehydrated sorbitol esterified with fatty acids and are commercially available as, for example, Tween® (Croda International LLC, WilmingtonDE) and Kolliphor® PS (BASF SE, Ludwigshafen, Germany). Polysorbate surfactant (PS) RBs include polysorbate 20 (e.g., Tween® 20), polysorbate 40 (e.g., Tween® 40), polysorbate 60 (e.g., Tween® 60), polysorbate 65 (e.g., Tween® 65), and polysorbate 80 (e.g., Tween® 80). The number following “polysorbate” relates to the major fatty acid in the molecule. For example, “20” indicates monolaurate and “80” indicates monooleate. Tween® 80 may also be referred to herein as T80, and other types of Tween® may be similarly named.

[0119] The method may also include drying the water-soluble complex to form a solid. The dried solid can then be redissolved in a suitable liquid.

[0120] This article focuses on the application of the molar ratio of drug compound to non-nutritive sugar to PSS surfactant (i.e., drug:sugar:PSS). The ratio of drug compound to non-nutritive sugar to PSS ranges from 1:1:1 to 1:12:12, or 1:1:1 to 1:10:10, or 1:1:1 to 1:5:5, or any 0.1 of the ratio of (moles of drug compound) to (moles of non-nutritive sugar) to (moles of PSS), i.e., drug:sugar:PSS, between 1:1.0:1.0 and 1:12.0:12.0.

[0121] This article focuses on the application of the molar ratio of drug compound to sugar to PXS surfactant (drug:sugar:PXS). The ratio of drug compound to sugar to PXS ranges from about 1:1:0.5 to 1:12:12, or 1:1:1 to 1:12:12, or 1:1:1 to 1:10:10, or 1:11:1 to 1:5:5, or any 0.1 amount between about 1:1.0:0.5 and about 1:12.0:12.0 (the number of moles of drug compound to the number of moles of sugar to the number of moles of PXS; i.e., drug:sugar:PXS).

[0122] This method can be used with a surfactant in conjunction with one or more solvents, or in the presence of an acid or buffer solution. The solvent used in this method can be a pure solvent, such as anhydrous ethanol, or a mixture of solvents as suggested herein, such as ethanol, water, and methanol. Sugars, pharmaceutical compounds, and solvents can be placed in a container with the surfactant, and the pH can then be adjusted until a homogeneous solution is formed. Preferably, the homogeneous solution remains stable for at least 30 minutes, more preferably at least 2 minutes, and even more preferably at least about 24 hours.

[0123] For administration, the powder form can be reconstituted at the place of manufacture, at the dispensing pharmacy, or by the patient in a liquid medium. The liquid medium can be water, a buffered aqueous solution, syrup, or an aqueous beverage, such as an energy drink or an electrolyte-rich beverage. For example, a water-soluble complex with improved water solubility can be reconstituted in, for example, sterile saline or another sterile liquid carrier and administered to the subject via subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravenous (iv), local, or oral routes (oral administration into the gastrointestinal tract or sublingual or oral administration). The water-soluble complex can also be formulated as a subcutaneous or intramuscular injection.

[0124] Suitable ingredients for formulating tablets or pills or other solid oral forms of the water-soluble complex may also include any or all of the following, such as corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol, titanium dioxide, and hydroxypropyl methylcellulose. Other compositions incorporated into the hydrogen-bonded and / or water-soluble complex may include or be in the form of oral stool softeners, flavorings, colorings, oral stimulants, and / or rectal suppositories.

[0125] The terms "sugar" and "non-nutritive sugar" are used to refer to sugars that are non-nutritive sweeteners. Non-nutritive sugars have a sweetness at least 50 times that of glucose and are essentially calorie-free. The non-nutritive sweetener sugar or "DTG" used in this article can be raspberry glycoside, dulcisin B (also known as neo-dulcisin C), stevia, neo-dulcisin A (also known as caracarcin A3), or caracarcin (a diterpenoid glycoside type with C...). 38 H 60 O 18 (chemical formula), n-octyl glucose, n-dodecyl-β-D-maltose (also known as dodecyl maltose or lauryl maltose), stevia (with C 44 H 70 O 23 (chemical formula) and steviol glycosides, for example, derived from stevia ( Stevia rebaudianaIt can also be any other sugar discussed herein. Although other stevia-like sugars are known, only those that are FDA GRAS-approved are considered for use in water-soluble complexes for administration to human subjects. Preferably, the sugar is one or more of raspberry glycoside, stevia, dulcitin B, carhariside, n-dodecyl-β-D-maltodextrin, or neohesperidin A, which can be used in any combination or arrangement. Any arrangement of these six listed sugars (two sugars, three sugars, etc.) is also of interest. The price of the sugar can be a factor in determining whether it is a commercially viable sugar for dissolving poorly soluble or soluble pharmaceutical compounds. Exemplary sugars used to prepare the “water-soluble complex” are raspberry glycoside, dulcitin A, dulcitin B, sucrose, D-fructose, sucralose, neodulcitin A, neodulcitin B, neodulcitin D, carhariin, stevia n-octyl glucose, or n-dodecyl-β-D-maltose glycoside, provided that when the sugar is raspberry glycoside, the compound is not praziquantel. Exemplary nonnutritive sugars include diterpenoid di-glycosides (referred to herein as DDG, which is a subset of DTG). Without being bound by theory, it is believed that when a sugar forms a water-soluble complex with a drug compound, a surfactant and a drug compound, or a sugar / surfactant / drug compound, a stable complex may be generated through non-covalent hydrogen bonding and optional hydrophobic-hydrophobic interactions such as van der Waals forces. As used herein, "sugar" can be dulcoside A, sucrose, D-fructose, sucralose, neodulcoside B, neodulcoside D, stevia, n-octyl glucose, Advantame®, neotame®, sematinine, saccharin, monk fruit, aspartame, acesulfame potassium (Ace-K), allulose, rhubarb glycoside, dulcoside B (also known as neodulcoside C), neodulcoside A (also known as carhariside A3), carhariside (DDG type), n-octyl glucose, and steviol glycosides, for example, derived from stevia. Although other stevia inulin-like sugars are known, only those that are FDA GRAS-approved or approved for use in Europe are considered for human use. Preferably, the sugar is one or more of rhubarb glycoside, steviol, dulcoside B, carhariside, or neodulcoside A, which can be used in any combination or arrangement. Also of interest is the arrangement of the listed sugars (two-sugar, three-sugar, etc.) in the formation of complexes. The price of the non-nutritive sugars is also a factor in determining whether they are commercially viable sugars for dissolving blood A1C and / or blood glucose regulating drug compounds. Also of interest are non-nutritive sugars that are not diterpenoid disaccharides but can be paired with the drug compounds described herein, including: ADVANTAME® – an aspartame analog; N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-aspartic acid]-L-phenylalanine-1-methyl ester (Otabe et al., “Advantame® – An Overview of Toxicity Data,” Food and Chemical Toxicity 49(S1): S2-S7, 2011). Advantame® has a low glycemic index (GI) and zero calories, but can cause insulin spikes.

[0126] NEOTAME® – marketed as Newtame® and an aspartame derivative, classified as an aspartic-derived dipeptide. Neotame® has a low glycemic index (GI) and zero calories, but can cause an insulin spike.

[0127] Somatostatin – also known as TALIN®, is derived from the winged arrowroot (Maranta spp.). Thaumatococcus danielli A mixture of sweet protein sematin I and sematin II.

[0128] Saccharin – also known as saccharin or benzosulfimide, and in salt forms such as sodium saccharin and calcium saccharin. It is marketed under the brand names Sweet & Low®, Sweet Twin®, Sweet'N Low®, and Necta Sweet®. Saccharin has a low glycemic index (GI) and zero calories, but can cause insulin spikes.

[0129] Sucralose – marketed under the name Splenda – is an organochlorine sweetener with the chemical name 1,6-dichloro-1,6-dideoxy- β - D -Fructofuranosyl-4-chloro-4-deoxy- α - D -Galacpyranoside (Schiffman et al., "Sucralose, A Synthetic Organochlorine Sweetener: Overview of Biological Issues," J. Toxicol Environ. Health B. Crit. Rev . 16(7): 399-451, 2013). Sucralose has a low glycemic index (GI) and zero calories, but can cause insulin spikes.

[0130] Monk fruit – also known as Siraitia grosvenorriSweeteners derived from swingle fruit, monk fruit, and monk fruit can be calorie-free. The FDA calls it saffron mandarin fruit extract (SGFE). The compounds that impart sweetness are mogrosides, which have a mogrol backbone and glucose units (glycosides) linked to it. They can be marketed under the trademarks Raw®, Lakanto®, PureLo®, Splenda® Monk Fruit Sweetener, SweetLeaf®, and Whole Earth® under the name Monk Fruit. SGFE does not raise blood sugar levels.

[0131] Aspartame – marketed under names like Nutrasweet, Equal, and Sugar Twin – does contain calories. Its chemical name is L-aspartic-L-phenylalanine methyl ester. It is a dipeptide composed of phenylalanine and aspartic acid. Aspartame has a low glycemic index (GI) and zero calories, but it can cause an insulin spike.

[0132] Acetylsulfamate – also known as Ace-K and marketed under the brand names Sweet One® and Sunett®. Ace-K has a low glycemic index (GI) and zero calories, but it can cause insulin spikes.

[0133] Allulose is a sugar naturally found in figs and raisins. It is also called D-psicose or D-allulose and has almost no calories. It does not affect insulin or blood sugar levels. (Tani et al., “Allulose for the attenuation of postprandial blood glucose levels in healthy humans: A systematic review and meta-analysis,”) PLoS One 18(4): e0281150, 2023.

[0134] The sweetness of non-nutritive sugars and table sugar (sucrose) is compared and summarized in the table below, obtained from the US FDA:

[0135] The complexation of drug compounds with non-nutritive sugars can be interpreted as a donor (sugar)-receptor (drug compound) interaction, such as host-guest chemistry between the drug compound and the sugar, which essentially allows the drug compound to capture the water solubility of the sugar.

[0136] If desired, polyethylene glycol (PEG) can optionally be added to liquid and powder formulations to further improve bioavailability. Typically, it is in the range of 2000-6000 Daltons, 3000-4500 Daltons, or 3200-3700 Daltons, as well as other pharmaceutically acceptable molecular weights used when formulating PEG with chemical compounds. Common commercially available forms of PEG have molecular weights of 3350, 4000, and 6000 Daltons. For example, PEG products can be polydisperse or monodisperse. If polydisperse, the molecular weight describes the weight-average molecular weight of the formulation. Depending on whether the formulation is in powder or liquid form, the weight ratio of PEG to the A1C-modifying compound can be between and include these values, such as 5:1, 6:1, 7:1, 8:1, 9:1, and 10:1. In one embodiment, the weight ratio is about 8:1.

[0137] For administration, the powder form can be reconstituted at the place of manufacture, at the dispensing pharmacy, or by the patient in a liquid medium. The liquid medium can be water, a buffered aqueous solution, a syrup, or an aqueous beverage, such as an energy drink or an electrolyte-rich beverage. For example, a water-soluble complex with improved water solubility can be reconstituted in sterile saline or another sterile liquid carrier and administered to the subject via subcutaneous (sc), intraperitoneal (ip), intramuscular (im), intravenous (iv), local, or oral routes (oral administration into the gastrointestinal tract or sublingual or oral administration).

[0138] Suitable ingredients for the formulation of tablets or pills, or other solid oral forms, of hydrogen-bonded and / or water-soluble complexes may include any or all of the following, such as corn starch, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, polyethylene glycol (PEG), titanium dioxide, and hydroxypropyl methylcellulose. Additional compositions incorporating the hydrogen-bonded and / or water-soluble complexes may include shaping agents, oral stool softeners, oral stimulants, and / or rectal suppositories.

[0139] Other methods for prolonging drug release are known, such as enteric-coated tablets, coating the complex with a slowly dissolving polymer (the polymer can be selected according to the desired length and / or thickness to change the drug release rate), encapsulating the complex in a gel capsule, encapsulating the complex in an insoluble matrix (e.g., Slow-K or Imdur Durules), encapsulating the complex in an erosive matrix (e.g., MST Continus, Phyllocontin Continus), and / or encapsulating the complex in a semi-permeable membrane. See, for example, “Pharmaceutical Issues when Crushing, Opening or Splitting Oral Dosage Forms,” Royal Pharmaceutical Society, June 2011. Other oral dosage forms that improve release include “extended-release drug products,” where the dosage form of the complex allows for a dose frequency that is at least two-fold lower than that provided in a non-extended-release form of a water-soluble complex. Examples of extended-release dosage forms include controlled-release, sustained-release, and / or long-acting drug products. Another type of oral dosage form that improves release is a delayed-release drug product. In delayed-release formulations, the complex dosage form releases one or more discrete portions of the drug or compound from the complex at a specified time rather than rapidly after administration. Enteric-coated dosage forms are common delayed-release products (e.g., enteric-coated aspirin and other NSAIDs (nonsteroidal anti-inflammatory drugs) are examples of coated drugs). Another modified release oral form of the complex of interest is the targeted-release drug product. This dosage form releases the drug complex at and / or near the intended physiological site of action. Another modified release oral dosage form of water-soluble complexes is the orally disintegrating tablet (ODT) or equivalent. ODTs have been developed to rapidly disintegrate in saliva after oral administration. Sugar-A1C-modifying compound complexes in ODT form can be used without the addition of water. The water-soluble complex is dispersed in saliva and swallowed with little or no water.

[0140] Any components can be packaged in the kit, individually in a single container, or mixed with each other. End users can reconstitute the components using the included diluent or a diluent of their choice. In addition to individual or mixed components, the kit may also include instructions for use, equipment for mixing and / or administering to subjects, storage containers, etc. Any components can be packaged in the kit, individually in a single container, or mixed with each other.

[0141] Another feature that can be imparted by improving the solubility of drugs / compounds is, as described in this article, the improved storage stability of water-soluble complexes.

[0142] In the examples used below, the same conditions were used unless otherwise specified. The water used was deionized distilled water. 95% ethanol (ACS spectrophotometric grade, unless otherwise specified) was used. High vacuum drying was performed at room temperature using, for example, an Edvards Model RV8 high vacuum pump with an IKA Model C-mag HS7 magnetic stirrer. In the examples below, a Heto Drywinner model #DW-1.0-60E freeze dryer was used to remove ethanol. A rotary evaporator, such as a Heidolph Basis Hei-VAP value (number 560-00000-01-1), can also be used to remove ethanol from the mixture, for example at 35°C. o The solid was produced by reducing the pressure at C bath temperature. The reagents used were as follows: Lispro insulin was purchased from Millipore Sigma (empirical formula C). 257 H 383 N 65 O 77 S6; Molecular weight 5.807.57 kDa; CAS number: 133107-64-9). Humalog® (a registered trademark of Eli Lilly and Company) is a commercially available insulin lispro.

[0143] Example 1 – Lispro Insulin and Carhariin

[0144] The following examples indicate that carhariside improves the solubility of lispro insulin.

[0145] Step 1: At ambient temperature, in a dried single-necked RB flask equipped with a magnetic stir bar and septum (flask cap), weigh 5 mg of lispro insulin (0.00086 mmol) and 6.93 mg of carhartoin (0.0086 mmol) (molar ratio 1:10) and dissolve in 2.0 mL of anhydrous ethanol (spectrometer grade, 95%). Stir the reaction mixture vigorously at room temperature for up to 30 min. The resulting solution is turbid. Dry the solution under high vacuum, maintaining below 30 °C for 1 hour to completely remove the ethanol. Then proceed with the freeze-drying process. Freeze-drying process: At approximately -30 °C, place the flask in a cold bath and rotate it in water until the walls are like thick ice. Then freeze-dry under vacuum using a freeze dryer. Maintain the temperature below 0 °C until the ice evaporates, thus obtaining a white solid (the carhartoin-insulin complex).

[0146] Step 2: Then, at room temperature in an RB flask equipped with a magnetic stir bar, dissolve 2.5 mg of the resulting white solid (1:0:10.0 molar ratio of insulin:caharicoside complex) in 0.3 mL of distilled water (DI). Stir the reaction mixture at ambient temperature for 30 min. The resulting solution (pH ~5.0) is considered clear and homogeneous.

[0147] The resulting white solid was dissolved in deionized water. The water-soluble complex was analyzed by NMR. See [link to NMR analysis]. Figure 1 NMR analysis confirmed the dissolution of the insulin:cacioside complex at a molar ratio of 1:0:10.0, as multiple insulin peaks were observed. These data indicate that insulin is soluble in water in the presence of carcioside.

[0148] Example 2 – Carhariin and Smegglutinin

[0149] In this embodiment, smegglutide free base (Astatech catalog number AT35750, CAS#: 910463-68-2, batch number: P180-01178, 0.005 g 99% purity) and carabinin were combined as follows to observe whether a complex could be formed. In this embodiment, 3.0 mg of smegglutide and 100 mg of carabinin were placed in a round-bottom flask containing 2.0 mL of 85% ethanol and stirred with a magnetic stir bar for 30 minutes at room temperature. Initially, a clear solution was observed to form at room temperature. After 30 minutes, solid particles were observed to form, and after 15 minutes, the solution became white and cloudy with the presence of solid particles. 2.0 mL of anhydrous methanol (99.8%) was added to the solution, and the solution was stirred for another 15 minutes. The solution remained white and cloudy. As shown in Example 1, a rotary evaporator was used to remove the ethanol and methanol. The material was dried until no further weight change was observed.

[0150] Add 2.0 mL of deionized water to the dried material obtained from ethanol / methanol (step 1) and stir at room temperature for 30 minutes. A clear, homogeneous solution was observed to form immediately. The sample was dried again using a rotary evaporator, but this time at 30°C, and also using a water bath. The sample was dried until no further weight change was observed. When analyzed by NMR, it was clear that smegglutinin and caracara glycoside formed a soluble complex. See also... Figure 2 Smegglutide sodium is considered insoluble in water and DMSO at 25 °C; it is soluble in 4-methylpyridine at a concentration of 8 mg / mL. The free base of smegglutide has a molecular weight of 4113.58. The complex remains soluble in aqueous solution for at least approximately 8 days.

[0151] Implementation Plan

[0152] The following are exemplary embodiments, as well as other embodiments described throughout this specification.

[0153] Implementation Scheme 1. A water-soluble complex comprising a sugar and a poorly soluble drug (PSD, also known as a drug compound), the complex comprising: a molar ratio of up to about 12 moles of sugar per mole of the poorly soluble drug, wherein the sugar is one or more of rhubarb glycoside, dulcisin B, dodecyl-β-D-maltodextrin, coixol or styraxin A, provided that the water-soluble complex increases the water solubility of the poorly soluble drug at 20°C by at least two (2), three (3), four (4) or five (5) times compared to the water solubility of the drug not in the water-soluble complex; and further provided that the maximum amount of sugar in a daily unit dose of the complex does not exceed about 10 mg / kg, and wherein the PSD is insulin.

[0154] Implementation Scheme 2. The water-soluble complex of Implementation Scheme 1, wherein PSD is insulin or an insulin analogue.

[0155] Implementation Scheme 3. A water-soluble complex of Implementation Scheme 1 or 2, wherein the PSD is rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or ultra-long-acting insulin.

[0156] Implementation Scheme 4. A water-soluble complex of any one of Implementation Schemes 1-3, wherein the sugar is raspberry glycoside, neohesperidin A, dodecyl-β-D-maltodextrin, dulcitin B, or coixol.

[0157] Implementation Scheme 5. The water-soluble complex of Implementation Scheme 4, wherein the sugar is raspberry glycoside or carabinin.

[0158] Implementation Scheme 6. A water-soluble complex of any one of Implementation Schemes 1-5, wherein the amount of sugar in a daily unit dose does not exceed 5 mg / kg.

[0159] Implementation Scheme 7. A water-soluble complex of any one of Implementation Schemes 1-5, wherein the amount of sugar in a daily unit dose does not exceed about 280 mg.

[0160] Implementation Scheme 8. A water-soluble complex of any one of Implementation Schemes 1-5, wherein the water-soluble complex contains PSD in a molar ratio of about 1:1 to about 1:10 moles of sugar.

[0161] Implementation Scheme 9. A water-soluble complex of any one of Implementation Schemes 1-5, wherein the water-soluble complex comprises a molar ratio of about 2 to about 10 moles of sugar per mole of PSD.

[0162] Implementation Scheme 10. The water-soluble complex of Implementation Scheme 9, wherein the water-soluble complex comprises a molar ratio of approximately 3 moles of sugar per mole of PSD.

[0163] Implementation Scheme 11. A water-soluble complex of any one of Implementation Schemes 1-5, wherein the water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

[0164] Implementation Scheme 12. A water-soluble complex of any one of Implementation Schemes 1-5, wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours.

[0165] Implementation Scheme 13. A dried form of the water-soluble complex of any one of Implementation Schemes 1-12, wherein the dried form is stable at 30 °C for at least 90 days.

[0166] Implementation Scheme 14. The water-soluble complex of any one of Implementation Schemes 1-13, wherein the water-soluble complex is in the form of powder, tablet, orally disintegrating tablet, capsule, liquid, gel, film, lozenge, effervescent powder or tablet, emulsion, or formulated for parenteral administration.

[0167] Implementation Scheme 15. The water-soluble complex of Implementation Scheme 14, wherein the formulation for parenteral administration is administered via intradermal, subcutaneous, intramuscular, intraperitoneal, intrathecal, intravenous, topical, or as a transdermal patch.

[0168] Implementation Scheme 16. The water-soluble complex of any one of Implementation Schemes 1-13, wherein the water-soluble complex is in the form of a film, effervescent powder or tablet, syrup, solution, elixir, emulsion, chewing gum, lollipop, sublingual drops, soft gel or tincture.

[0169] Implementation Scheme 17. A water-soluble complex comprising a sugar and a poorly soluble drug (PSD), wherein the water-soluble complex comprises: a molar ratio of about 1 to 12 moles of sugar per mole of PSD, wherein the sugar is one or more of rhubarb glycoside, neohesperidin A, dulcitin B, dodecyl-β-D-maltodextrin (DDM) or coixol; wherein the water-soluble complex is stable in water at pH 8.5 and pH 4.0 for at least 2 hours, respectively; provided that the water-soluble complex has at least two (2) times, three (3) times, four (4) times or five (5) times the water solubility of PSD at 20°C compared to the water solubility of PSD not in the water-soluble complex; and further provided that the maximum amount of sugar in a daily unit dose of the water-soluble complex does not exceed about 280 mg, wherein the PSD is insulin.

[0170] Implementation Scheme 18. A method for preparing a water-soluble complex comprising a sugar and a poorly soluble drug substance (PSD), the method comprising the following steps: In at least 85% ethanol, sugar and PSD are mixed at a molar ratio of about 1 to about 12 moles of sugar per mole of PSD 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 said sugar is one or more of raspberry glycoside, neohesperidin A, dulcitin B, dodecyl-β-D-maltodextrin (DDM) or coixol; wherein the mixing step is optionally carried out with a pharmaceutically acceptable acid, and wherein the water-soluble complex is optionally dried, wherein the PSD is insulin.

[0171] Implementation Scheme 19. The method of Implementation Scheme 18, wherein the sugar is raspberry glycoside or carabinin.

[0172] Implementation Scheme 20. The method of either Implementation Scheme 18 or 19, wherein PSD is short-acting insulin, intermediate-acting insulin or long-acting insulin.

[0173] Implementation Scheme 21. The method of Implementation Scheme 18, wherein the method further includes drying the water-soluble aggregate.

[0174] Implementation Scheme 22. The method of Implementation Scheme 21, wherein the dried water-soluble aggregate is redissolved in a liquid.

[0175] Implementation Scheme 23. The method of Implementation Scheme 18, wherein the mixing step is carried out in the presence of a sufficient amount of pharmaceutically acceptable acid to dissolve the reaction mixture and make it homogeneous and clear.

[0176] Implementation Scheme 24. The method of Implementation Scheme 23, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

[0177] Implementation Scheme 25. The method of Implementation Scheme 18, wherein the formed water-soluble complex comprises a molar ratio of about 1 to about 10 moles of sugar per mole of PSD.

[0178] Implementation Scheme 26. The method of Implementation Scheme 25, wherein the sugar is raspberry glycoside or carabinin.

[0179] Implementation Scheme 27. The method of Implementation Scheme 25, wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 5 moles of sugar per mole of PSD.

[0180] Implementation Scheme 28. The method of Implementation Scheme 27, wherein the sugar is raspberry glycoside or carabinin.

[0181] Implementation Scheme 29. The method of Implementation Scheme 25, wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of sugar per mole of PSD.

[0182] Implementation Scheme 30. The method of Implementation Scheme 29, wherein the sugar is raspberry glycoside or carabinin.

[0183] Implementation Scheme 31. The method of Implementation Scheme 25, wherein the formed water-soluble complex comprises a molar ratio of approximately 8 moles of sugar per mole of PSD.

[0184] Implementation Scheme 32. The method of Implementation Scheme 31, wherein the sugar is raspberry glycoside or carabinin.

[0185] Implementation Scheme 33. The method of Implementation Scheme 18, wherein the formed water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

[0186] Implementation Scheme 34. The method of Implementation Scheme 18, wherein the formed water-soluble complex is stable in water at pH 4 for at least 2 hours.

[0187] Implementation Scheme 35. The method of Implementation Scheme 21, wherein the method further includes drying the water-soluble complex by freeze-drying or lyophilization.

[0188] Implementation Scheme 36. The method of Implementation Scheme 35, wherein the dried water-soluble complex is formulated in a pill or a pharmaceutically acceptable liquid.

[0189] Implementation Scheme 1A. A water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, the complex comprising: The molar ratio of non-nutritive sugars per mole of the drug compound is up to about 12 moles, wherein the non-nutritive sugars are one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitin B, dodecyl-β-D-maltodextrin, coixol, or neohesperidin A. The conditions are that the water-soluble complex has at least a two (2)-fold increase in the water solubility of the drug compound at 20°C compared to the water solubility of the drug compound not in the water-soluble complex, and / or has at least one improved pharmacokinetic property (e.g., C10). max Reaching C max (Time, stability, duration, etc.); and Furthermore, the condition is that the maximum amount of sugar in the daily unit dose of the water-soluble complex does not exceed about 10 mg / kg, wherein the pharmaceutical compound is a peptide or small compound for lowering blood glucose and / or blood A1C in the subject, and the pharmaceutical compound is insulin, insulin analog, natural insulin variant, GLP-1 receptor agonist, incretin mimic, GIP agonist, amylin agonist, glucagon agonist or a salt thereof.

[0190] Implementation Scheme 2A. The water-soluble complex of Implementation Scheme 1A, wherein the pharmaceutical compound is an insulin analog, insulin, or a natural insulin variant.

[0191] Implementation Scheme 3A. The water-soluble complex of Implementation Scheme 2A, wherein the insulin analogue is lispro insulin, aspart insulin, glutathione insulin, admelog insulin, NPH insulin, protamine zinc insulin, glargine insulin, detemir insulin, or degludec insulin.

[0192] Implementation Scheme 4A. The water-soluble complex of Implementation Scheme 1A, wherein the pharmaceutical compound is a rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or ultra-long-acting insulin.

[0193] Implementation Scheme 5A. A water-soluble complex of Implementation Scheme 1A, wherein the pharmaceutical compound is a GLP-1 receptor agonist.

[0194] Implementation Scheme 6A. The water-soluble complex of Implementation Scheme 5A, wherein the GLP-1 receptor agonist is semaglutide, telposide, amiklipine, oxaliplatin, abiglutide, benaglutide, caglionetin, CagriSema, CT996, dapagliflozin, afenotinide, HM15211, lixisenatide, peptidoglycan, retaglutide, SCO-094, sovoglutide, WK2735, mascara, PEG-profenatide (PEX168), liraglutide, dulaglutide, ezenatide, or a salt thereof.

[0195] Implementation Scheme 7A. A water-soluble complex of Implementation Scheme 1A, wherein the pharmaceutical compound is a GIP agonist.

[0196] Implementation Scheme 8A. The water-soluble complex of Implementation Scheme 7A, wherein the GIP agonist is HM15211, rapaglutide, SCO-094, telpoglycinide, WK2735 or ZP6590.

[0197] Implementation Scheme 9A. The water-soluble complex of Implementation Scheme 1A, wherein the pharmaceutical compound is a glucagon agonist.

[0198] Implementation Scheme 10A. The water-soluble complex of Implementation Scheme 9A, wherein the glucagon agonist is affinoside, HM15211, mascara, pevitide, or sovorutide.

[0199] Implementation Scheme 11A. A water-soluble complex of Implementation Scheme 1A, wherein the pharmaceutical compound is an amylin agonist.

[0200] Implementation Scheme 12A. The water-soluble complex of Implementation Scheme 11A, wherein the amylin agonist is AZD6234, caglitinide, CagriSema, CT388, a long-acting amylin agonist, amiklipine, or ZP8396.

[0201] Implementation Scheme 13A. A water-soluble complex of any one of Implementation Schemes 1A-12A, wherein the non-nutritive sugar is raspberry glycoside, neohesperidin A, dodecyl-β-D-maltodextrin, dulcitin B, or coixol.

[0202] Implementation Scheme 14A. The water-soluble complex of Implementation Scheme 13A, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0203] Implementation scheme 15A. A water-soluble complex of any one of implementation schemes 1A-14A, wherein the amount of non-nutritive sugar in the daily unit dose does not exceed 5 mg / kg of subject body weight.

[0204] Implementation scheme 16A. A water-soluble complex of any one of implementation schemes 1A-14A, wherein the amount of non-nutritive sugars in a daily unit dose does not exceed about 280 mg.

[0205] Implementation Scheme 17A. A water-soluble complex of any one of Implementation Schemes 1A-14A, wherein the water-soluble complex comprises a molar ratio of a pharmaceutical compound to a non-nutritive sugar of about 1:1 to about 1:10 (pharmaceutical compound: non-nutritive sugar).

[0206] Implementation Scheme 18A. A water-soluble complex of any one of Implementation Schemes 1A-14A, wherein the water-soluble complex comprises a molar ratio of about 1:12 to about 10 moles of non-nutritive sugars per mole of pharmaceutical compound (non-nutritive sugar: pharmaceutical compound).

[0207] Implementation Scheme 19A. The water-soluble complex of Implementation Scheme 18A, wherein the water-soluble complex comprises a molar ratio of approximately 3 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0208] Implementation Scheme 20A. A water-soluble complex of any one of Implementation Schemes 1A-14A, wherein the water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

[0209] Implementation Scheme 21A. A water-soluble complex of any one of Implementation Schemes 1A-14A, wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours.

[0210] Implementation Scheme 22A. The dried form of the water-soluble complex of any one of Implementation Schemes 1A-19A, wherein the dried form of the water-soluble complex is stable at 30°C for at least 90 days.

[0211] Implementation Scheme 23A. A water-soluble complex of any one of Implementation Schemes 1A-19A, wherein the water-soluble complex is formulated as a powder, tablet, orally disintegrating tablet, capsule, liquid, gel, film, lozenge, effervescent powder or tablet, emulsion, or formulated for parenteral administration.

[0212] Implementation Scheme 24A. The water-soluble complex of Implementation Scheme 23A, wherein the water-soluble complex is formulated for application via intradermal, subcutaneous, intramuscular, intraperitoneal, intrathecal, intravenous, topical (e.g., gel, cream or ointment) or as a transdermal patch.

[0213] Implementation Scheme 25A. A water-soluble complex of any one of Implementation Schemes 1A-22A, wherein the water-soluble complex is in the form of a film, effervescent powder or tablet, syrup, solution, elixir, emulsion, chewing gum, lollipop, sublingual drops, soft gel or tincture.

[0214] Implementation Scheme 26A. A water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, the water-soluble complex comprising: A molar ratio of approximately 1 to 12 moles of non-nutritive sugars per mole of the drug compound, wherein the non-nutritive sugars are one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitin B, dodecyl-β-D-maltodextrin, coixol, or neohesperidin A; The water-soluble complex is stable in water for at least 2 hours at pH 8.5 and pH 4.0, respectively. The condition is that the water-soluble complex has at least a two (2)-fold increase in water solubility at 20 °C compared to the water solubility of the drug compound not in the water-soluble complex, or has at least one improved pharmacokinetic property (e.g., C10). max Reaching C max (Time, stability, duration, etc.); and Furthermore, the condition is that the maximum amount of non-nutritive sugar in the daily unit dose of the water-soluble complex does not exceed about 280 mg; wherein the pharmaceutical compound is a peptide or small compound that lowers the subject's blood glucose and / or blood A1C, and wherein the pharmaceutical compound is insulin, an insulin analog, a natural insulin variant, a GLP-1 receptor agonist, an incretin mimic, a GIP agonist, an amylin agonist, a glucagon agonist, or a salt thereof.

[0215] Implementation Scheme 27A. A method for preparing a water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, the method comprising the steps of: mixing the non-nutritive sugar and the pharmaceutical compound in at least 85% ethanol at a molar ratio of about 1 to about 12 moles of sugar per mole of pharmaceutical compound until dissolved, thereby forming a water-soluble complex, wherein the formation of the water-soluble complex can be determined by nuclear magnetic resonance spectroscopy (NMR), wherein the non-nutritive sugar is ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, or suspensa. One or more of the following: glycoside, dulcitin B, dodecyl-β-D-maltodextrin, carhariside, or neohesperidin A; wherein the mixing step is optionally carried out with a pharmaceutically acceptable acid; and the water-soluble complex is dried and dissolved in water, wherein the pharmaceutical compound is a peptide or small compound that lowers the subject's blood glucose and / or blood A1C, and wherein the pharmaceutical compound is insulin, an insulin analog, a natural insulin variant, a GLP-1 receptor agonist, an incretin mimic, a GIP agonist, an amylin agonist, a glucagon agonist, or a salt thereof.

[0216] Implementation Scheme 28A. The method of Implementation Scheme 27A, wherein the pharmaceutical compound is rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or ultra-long-acting insulin.

[0217] Implementation Scheme 29A. The method of Implementation Scheme 27A, wherein the pharmaceutical compound is an insulin analog, insulin, or a variant of natural insulin.

[0218] Implementation scheme 30A. The method of implementation scheme 29A, wherein the insulin analogue is lispro insulin, aspart insulin, glutathione insulin, admelog insulin, NPH insulin, protamine zinc insulin, glargine insulin, detemir insulin, or degludec insulin.

[0219] Implementation scheme 31A. The method of any one of implementation scheme 27A, wherein the pharmaceutical compound is a GLP-1 receptor agonist.

[0220] Implementation Scheme 32A. The method of Implementation Scheme 31A, wherein the GLP-1 receptor agonist is semaglutide, telposide, amiklipine, oxaliplatin, abiglutide, benaglutide, caglionetin, CagriSema, CT996, dapagliflozin, afenotinide, HM15211, lixisenatide, peptidoglycan, retaglutide, SCO-094, sovoglutide, WK2735, mascara, PEG-profenatide (PEX168), liraglutide, dulaglutide, ezenatide, or a salt thereof.

[0221] Implementation scheme 33A. The method of implementation scheme 27A, wherein the pharmaceutical compound is a GIP agonist.

[0222] Implementation scheme 34A. The method of implementation scheme 33A, wherein the GIP agonist is HM15211, rapaglutide, SCO-094, telpoglycinide, WK2735 or ZP6590.

[0223] Implementation scheme 35A. The method of any one of implementation scheme 27A, wherein the pharmaceutical compound is a glucagon agonist.

[0224] Implementation Scheme 36A. The method of Implementation Scheme 35A, wherein the glucagon agonist is affinoside, HM15211, mascara, pevitide, or sovorutide.

[0225] Implementation Scheme 37A. The method of any one of Implementation Scheme 27A, wherein the pharmaceutical compound is an amylin agonist.

[0226] Implementation Scheme 38A. The method of Implementation Scheme 37A, wherein the amylin agonist is AZD6234, caglitinide, CagriSema, CT388, a long-acting amylin agonist, amiklipine, or ZP8396.

[0227] Implementation Scheme 39A. The method of Implementation Scheme 27A, wherein the method further includes drying the water-soluble complex after dissolving it in water.

[0228] Implementation Scheme 40A. The method of Implementation Scheme 39A, wherein the dried water-soluble complex is redissolved in a liquid.

[0229] Implementation Scheme 41A. The method of Implementation Scheme 27A, wherein the mixing step is carried out in the presence of a sufficient amount of pharmaceutically acceptable acid to dissolve the reaction mixture and impart homogeneity and clarity to it.

[0230] Implementation Scheme 42A. The method of Implementation Scheme 41A, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

[0231] Implementation Scheme 43A. The method of Implementation Scheme 27A, wherein the formed water-soluble complex comprises a molar ratio of about 1 to about 10 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0232] Implementation scheme 44A. The method of implementation scheme 43A, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0233] Implementation Scheme 45A. The method of Implementation Scheme 43A, wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 5 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0234] Implementation Scheme 46A. The method of Implementation Scheme 45A, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0235] Implementation Scheme 47A. The method of Implementation Scheme 43A, wherein the formed water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0236] Implementation Scheme 48A. The method of Implementation Scheme 47A, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0237] Implementation scheme 49A. The method of implementation scheme 43A, wherein the water-soluble complex formed comprises a molar ratio of approximately 8 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0238] Implementation scheme 50A. The method of implementation scheme 49A, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0239] Implementation scheme 51A. The method of implementation scheme 27A, wherein the formed water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

[0240] Implementation scheme 52A. The method of implementation scheme 27A, wherein the formed water-soluble complex is stable in water at pH 4 for at least 2 hours.

[0241] Implementation Scheme 53A. The method of Implementation Scheme 39A, wherein drying the water-soluble complex comprises freeze-drying or lyophilization.

[0242] Implementation Scheme 54A. The method of Implementation Scheme 53A, wherein a dried water-soluble complex is formulated in a pill or a pharmaceutically acceptable liquid.

[0243] Implementation Scheme 55A. A method for treating a subject with type 1 diabetes (TD1), type 2 diabetes (TDI), obesity (weight loss), MASH, glycemic control, prediabetes, a condition characterized by impaired fasting glucose or impaired glucose tolerance, α- and β-cell dysfunction, and / or a condition producing a suboptimal incretin effect, the method comprising administering to said subject a water-soluble complex of any one of Implementation Schemes 1A-21A in a therapeutically effective amount.

[0244] Implementation Scheme 56A. Use of the water-soluble complex of any one of Implementation Schemes 1A-21A in the preparation of a medicament for the treatment of type 1 diabetes (TD1), type 2 diabetes (TDI), obesity (weight loss), MASH, glycemic control, prediabetes, conditions characterized by impaired fasting glucose or impaired glucose tolerance, α- and β-cell dysfunction and / or conditions producing suboptimal incretin effects.

[0245] Implementation Scheme 1B. A water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, the complex comprising: a molar ratio of up to about 12 moles of non-nutritive sugar per mole of pharmaceutical compound, wherein said non-nutritive sugar is one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitidine B, dodecyl-β-D-maltodextrin, coixol, or neohesperidin A, provided that the water-soluble complex has at least two (2) times greater water solubility of the pharmaceutical compound at 20 °C compared to the water solubility of the pharmaceutical compound not in the water-soluble complex, or has an improved pharmacokinetic property; and further provided that the maximum amount of non-nutritive sugar in a daily unit dose of the water-soluble complex does not exceed about 10 mg / kg, wherein the drug compound is used to lower blood glucose and / or reduce blood A1C in the subject, and the drug compound is insulin, insulin analog, natural insulin variant, GLP-1 receptor agonist, incretin mimic, GIP agonist, amylin agonist, glucagon agonist or a salt thereof.

[0246] Implementation Scheme 2B. The water-soluble complex of Implementation Scheme 1B further comprises a nonionic surfactant.

[0247] Implementation Scheme 3B. The water-soluble complex of Implementation Scheme 1B, wherein the pharmaceutical compound is an insulin analog, insulin, or a variant of natural insulin.

[0248] Implementation Scheme 4B. The water-soluble drug complex of Implementation Scheme 3B, wherein the insulin analogue is lispro insulin, aspart insulin, glutathione insulin, admelog, NPH insulin, protamine zinc insulin, glargine insulin, detemir insulin, or degludec insulin.

[0249] Implementation Scheme 5B. A water-soluble complex of any one of Implementation Scheme 3 or 4, wherein the pharmaceutical compound is a rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or ultra-long-acting insulin.

[0250] Implementation Scheme 6B. A water-soluble complex of Implementation Scheme 1B, wherein the pharmaceutical compound is a GLP-1 receptor agonist.

[0251] Implementation Scheme 7B. The water-soluble complex of Implementation Scheme 6B, wherein the GLP-1 receptor agonist is semaglutide, telposide, amiklipine, oxaliplatin, abiglutide, benaglutide, caglionetin, CagriSema, CT996, dapagliflozin, afenotinide, HM15211, lixisenatide, peptidoglycan, retaglutide, SCO-094, sovoglutide, WK2735, mascara, PEG-profenatide (PEX168), liraglutide, dulaglutide, ezenatide, or a salt thereof.

[0252] Implementation Scheme 8B. A water-soluble complex of Implementation Scheme 1B, wherein the pharmaceutical compound is a GIP agonist.

[0253] Implementation Scheme 9B. A water-soluble complex of Implementation Scheme 8B, wherein the GIP agonist is HM15211, rapaglutide, SCO-094, telpoglycinide, WK2735 or ZP6590.

[0254] Implementation Scheme 10B. The water-soluble complex of Implementation Scheme 1B, wherein the pharmaceutical compound is a glucagon agonist.

[0255] Implementation Scheme 11B. The water-soluble complex of Implementation Scheme 10B, wherein the glucagon agonist is affinoside, HM15211, mascara, pevitide, or sovorutide.

[0256] Implementation Scheme 12B. The water-soluble complex of Implementation Scheme 1B, wherein the pharmaceutical compound is an amylin agonist.

[0257] Implementation Scheme 13B. The water-soluble complex of Implementation Scheme 12B, wherein the amylin agonist is AZD6234, caglitinide, CagriSema, CT388, a long-acting amylin agonist, amiklipine, or ZP8396.

[0258] Implementation Scheme 14B. A water-soluble complex of any one of Implementation Schemes 1B-13B, wherein the non-nutritive sugar is raspberry glycoside, neohesperidin A, dodecyl-β-D-maltodextrin, dulcitin B, or coixol.

[0259] Implementation Scheme 15B. The water-soluble complex of Implementation Scheme 14B, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0260] Implementation scheme 16B. A water-soluble complex of any one of implementation schemes 1B-15B, wherein the non-nutritive sugar content in the daily unit dose does not exceed 5 mg / kg of subject body weight.

[0261] Implementation scheme 17B. A water-soluble complex of any one of implementation schemes 1B-15B, wherein the non-nutritive sugar content in a daily unit dose does not exceed about 280 mg.

[0262] Implementation Scheme 18B. A water-soluble complex of any of Implementation Schemes 1B-15B, wherein the water-soluble complex comprises a molar ratio of drug compound to non-nutritive sugar of about 1:1 to about 1:10 (drug compound: sugar).

[0263] Implementation Scheme 19B. A water-soluble complex of any one of Implementation Schemes 1B-15B, wherein the water-soluble complex comprises a molar ratio of about 2 to about 10 moles of pharmaceutical compound / sugar.

[0264] Implementation Scheme 20B. The water-soluble complex of claim 19B, wherein the water-soluble complex comprises a molar ratio of about 3 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0265] Implementation Scheme 21B. A water-soluble complex of any one of Implementation Schemes 1B-15B, wherein the water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

[0266] Implementation Scheme 22B. A water-soluble complex of any one of Implementation Schemes 1B-15B, wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours.

[0267] Implementation Scheme 23B. The dried form of the water-soluble complex of any one of Implementation Schemes 1B-20B, wherein the water-soluble complex is stable at 30°C for at least 90 days when dried.

[0268] Implementation Scheme 24B. A water-soluble complex of any one of Implementation Schemes 1B-20B, wherein the water-soluble complex is formulated as a powder, tablet, orally disintegrating tablet, capsule, liquid, gel, film, lozenge, effervescent powder or tablet, emulsion, or for parenteral administration.

[0269] Implementation Scheme 25B. The water-soluble complex of Implementation Scheme 24B, wherein the water-soluble complex is formulated for application via intradermal, subcutaneous, intramuscular, intraperitoneal, intrathecal, intravenous, topical (e.g., gel, lotion, spray or inhalation form) or as a transdermal patch.

[0270] Implementation Scheme 26B. A water-soluble complex of any one of Implementation Schemes 1B-25B, wherein the water-soluble complex is in the form of a film, effervescent powder or tablet, syrup, solution, elixir, emulsion, chewing gum, lollipop, sublingual drops, soft gel or tincture.

[0271] Implementation Scheme 27B. A water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, the water-soluble complex comprising: a molar ratio of about 1 to 12 moles of non-nutritive sugar per mole of pharmaceutical compound, wherein the non-nutritive sugar is one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitidine B, dodecyl-β-D-maltodextrin, coixol, or neohesperidin A; wherein the water-soluble complex is stable in water at pH 8.5 and / or pH 4.0 for at least 2 hours; provided that the water-soluble complex has at least a two (2)-fold increase in water solubility at 20 °C compared to the pharmaceutical compound not present in the water-soluble complex, and / or at least one improved pharmacokinetic property; and further provided that the non-nutritive sugar in a daily unit dose of the water-soluble complex does not exceed about 280 mg, wherein the drug compound is used to lower the subject's blood glucose and / or blood A1C, and the drug compound is insulin, an insulin analog, a natural insulin variant, a GLP-1 receptor agonist, an incretin mimic, a GIP agonist, an amylin agonist, a glucagon agonist, or a salt thereof.

[0272] Implementation Scheme 28B. A method for preparing a water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, the method comprising the steps of: a) mixing one or more solvents, a non-nutritive sugar, and a pharmaceutical compound, wherein the molar ratio of the non-nutritive sugar to the pharmaceutical compound is about 1 to about 12 moles of non-nutritive sugar per mole of pharmaceutical compound, wherein the formation of the water-soluble complex can be determined by nuclear magnetic resonance spectroscopy (NMR), and wherein the non-nutritive sugar is one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitidine B, dodecyl-β-D-maltose glycoside, coixol, or neohesperidin A; and wherein the mixing step is optionally carried out with a pharmaceutically acceptable acid and / or a nonionic surfactant; and b) The water-soluble complex is dried and dissolved in water, wherein the pharmaceutical compound is a peptide or small compound for lowering blood glucose and / or blood A1C in a subject, and wherein the pharmaceutical compound for lowering blood glucose and / or blood A1C in a subject is insulin, an insulin analog, a natural insulin variant, a GLP-1 receptor agonist, an incretin mimic, a GIP agonist, an amylin agonist, a glucagon agonist, or a salt thereof.

[0273] Implementation Scheme 29B. The method of Implementation Scheme 28B, wherein the method further includes adding a nonionic surfactant to the solvent of step a).

[0274] Implementation scheme 30B. The method of implementation scheme 28B, wherein the pharmaceutical compound is rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin or ultra-long-acting insulin.

[0275] Implementation Scheme 31B. The method of Implementation Scheme 28B, wherein the pharmaceutical compound is an insulin analog, natural insulin, or an insulin variant.

[0276] Implementation Scheme 32B. The method of Implementation Scheme 31B, wherein the insulin analogue is lispro insulin, aspart insulin, glutathione insulin, admelog insulin, NPH insulin, protamine zinc insulin, glargine insulin, detemir insulin, or degludec insulin.

[0277] Implementation scheme 33B. The method of implementation scheme 28B, wherein the pharmaceutical compound is a GLP-1 receptor agonist.

[0278] Implementation Scheme 34B. The method of Implementation Scheme 33B, wherein the GLP-1 receptor agonist is semaglutide, telposide, amiklipine, oxaliplatin, abiglutide, benaglutide, caglionetin, CagriSema, CT996, dapagliflozin, afenotinide, HM15211, lixisenatide, peptidylcholine, retaglutide, SCO-094, sovoglutide, WK2735, mascara, PEG-profenatide (PEX168), liraglutide, dulaglutide, ezenatide, or a salt thereof.

[0279] Implementation scheme 35B. The method of claim 28B, wherein the pharmaceutical compound is a GIP agonist.

[0280] Implementation scheme 36B. The method of implementation scheme 35B, wherein the GIP agonist is HM15211, rapaglutide, SCO-094, telpoglycinide, WK2735 or ZP6590.

[0281] Implementation scheme 37B. The method of implementation scheme 28B, wherein the pharmaceutical compound is a glucagon agonist.

[0282] Implementation Scheme 38B. The method of Implementation Scheme 37B, wherein the glucagon agonist is affinoside, HM15211, mascara, pevitide or sovorutide.

[0283] Implementation Scheme 39B. The method of Implementation Scheme 28B, wherein the pharmaceutical compound is an amylin agonist.

[0284] Implementation Scheme 40B. The method of Implementation Scheme 39B, wherein the amylin agonist is AZD6234, caglitinide, CagriSema, CT388, a long-acting amylin agonist, amiklipine, or ZP8396.

[0285] Implementation Scheme 41B. The method of Implementation Scheme 28B, wherein the method further includes drying the dissolved water-soluble complex in step b).

[0286] Implementation Scheme 42B. The method of Implementation Scheme 41B, wherein the dried water-soluble complex is redissolved in a liquid.

[0287] Implementation Scheme 43B. The method of Implementation Scheme 28B, wherein step a) comprises a sufficient amount of pharmaceutically acceptable acid to dissolve the reaction mixture and impart homogeneity and clarity to it.

[0288] Implementation Scheme 44B. The method of Implementation Scheme 43B, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

[0289] Implementation Scheme 45B. The method of Implementation Scheme 28B, wherein the water-soluble complex comprises a molar ratio of about 1 to about 10 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0290] Implementation Scheme 46B. The method of Implementation Scheme 45B, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0291] Implementation Scheme 47B. The method of Implementation Scheme 45B, wherein the water-soluble complex comprises a molar ratio of about 2 to about 5 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0292] Implementation Scheme 48B. The method of Implementation Scheme 47B, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0293] Implementation Scheme 49B. The method of Implementation Scheme 45B, wherein the water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0294] Implementation scheme 50B. The method of implementation scheme 49B, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0295] Implementation scheme 51B. The method of implementation scheme 45B, wherein the water-soluble complex comprises a molar ratio of about 8 moles of non-nutritive sugars per mole of pharmaceutical compound.

[0296] Implementation scheme 52B. The method of implementation scheme 51B, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

[0297] Implementation scheme 53B. The method of implementation scheme 28B, wherein the water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

[0298] Implementation scheme 54B. The method of implementation scheme 28B, wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours.

[0299] Implementation scheme 55B. The method of implementation scheme 41B, wherein the method further includes drying the water-soluble complex by freeze-drying or lyophilization.

[0300] Implementation Scheme 56B. The method of Implementation Scheme 55B, wherein a dried water-soluble complex is formulated in a pill or a pharmaceutically acceptable liquid.

[0301] Implementation Scheme 57B. A method for treating a subject with type 1 diabetes (TD1), type 2 diabetes (TDI), obesity (weight loss), MASH, glycemic control, prediabetes, a condition characterized by impaired fasting glucose or impaired glucose tolerance, α- and β-cell dysfunction, and / or a condition producing a suboptimal incretin effect, the method comprising administering to said subject a water-soluble complex of any one of Implementation Schemes 1B-27B in a therapeutically effective amount.

[0302] Implementation Scheme 58B. Use of the water-soluble complex of any one of Implementation Schemes 1B-27B in the preparation of a medicament for the treatment of type 1 diabetes (TD1), type 2 diabetes (TDI), obesity (weight loss), MASH, glycemic control, prediabetes, conditions characterized by impaired fasting glucose or impaired glucose tolerance, α- and β-cell dysfunction and / or conditions producing suboptimal incretin effects.

Claims

1. A water-soluble complex comprising non-nutritive sugars and pharmaceutical compounds, the complex comprising: The molar ratio of non-nutritive sugars per mole of the drug compound is up to about 12 moles, wherein the non-nutritive sugars are one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitin B, dodecyl-β-D-maltodextrin, coixol, or neohesperidin A. The condition is that, compared to the water solubility of the drug compound not in the water-soluble complex, the water solubility of the drug compound at 20 °C is increased by at least two (2) times, or it has an improved pharmacokinetic property; and Furthermore, the condition is that the maximum amount of non-nutritive sugar in the daily unit dose of the water-soluble complex does not exceed about 10 mg / kg, wherein the pharmaceutical compound is used to lower the subject's blood glucose and / or blood A1C, and the pharmaceutical compound is insulin, an insulin analog, a natural insulin variant, a GLP-1 receptor agonist, an incretin mimic, a GIP agonist, an amylin agonist, a glucagon agonist, or a salt thereof.

2. The water-soluble complex of claim 1 further comprises a nonionic surfactant.

3. The water-soluble complex of claim 1, wherein the pharmaceutical compound is an insulin analog, insulin, or a natural insulin variant.

4. The water-soluble drug complex of claim 3, wherein the insulin analogue is lispro insulin, aspart insulin, glutathione insulin, admelog, NPH insulin, protamine zinc insulin, glargine insulin, detemir insulin, or degludec insulin.

5. The water-soluble complex of any one of claims 3 or 4, wherein the pharmaceutical compound is rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or ultra-long-acting insulin.

6. The water-soluble complex of claim 1, wherein the pharmaceutical compound is a GLP-1 receptor agonist.

7. The water-soluble complex of claim 6, wherein the GLP-1 receptor agonist is semaglutide, telposide, amiklipine, oxaliplatin, abiglutide, benaglutide, caglionetin, CagriSema, CT996, dapagliflozin, efenoxetine, HM15211, lixisenatide, peptidoglycan, retaglutide, SCO-094, sovoglutide, WK2735, mascara, PEG-profenatide (PEX168), liraglutide, dulaglutide, ezenatide, or a salt thereof.

8. The water-soluble complex of claim 1, wherein the pharmaceutical compound is a GIP agonist.

9. The water-soluble complex of claim 8, wherein the GIP agonist is HM15211, rapaglutide, SCO-094, telpoglycinide, WK2735, or ZP6590.

10. The water-soluble complex of claim 1, wherein the pharmaceutical compound is a glucagon agonist.

11. The water-soluble complex of claim 10, wherein the glucagon agonist is affinoside, HM15211, mascara, pevitide, or sovorutide.

12. The water-soluble complex of claim 1, wherein the pharmaceutical compound is an amylin agonist.

13. The water-soluble complex of claim 12, wherein the amylin agonist is AZD6234, caglitinide, CagriSema, CT388, a long-acting amylin agonist, amiklipine, or ZP8396.

14. The water-soluble complex of any one of claims 1-13, wherein the non-nutritive sugar is raspberry glycoside, neohesperidin A, dodecyl-β-D-maltodextrin, dulcitin B, or coixol.

15. The water-soluble complex of claim 14, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

16. The water-soluble complex of any one of claims 1-15, wherein the non-nutritive sugar content in the daily unit dose does not exceed 5 mg / kg of the subject's body weight.

17. The water-soluble complex of any one of claims 1-15, wherein the non-nutritive sugar content in a daily unit dose does not exceed about 280 mg.

18. The water-soluble complex of any one of claims 1-15, wherein the water-soluble complex comprises a molar ratio of the pharmaceutical compound to the non-nutritive sugar of about 1:1 to about 1:10 (pharmaceutical compound: non-nutritive sugar).

19. The water-soluble complex of any one of claims 1-15, wherein the water-soluble complex comprises a molar ratio of about 2 to about 10 moles of non-nutritive sugars per mole of pharmaceutical compound.

20. The water-soluble complex of claim 19, wherein the water-soluble complex comprises a molar ratio of about 3 moles of non-nutritive sugars per mole of pharmaceutical compound.

21. The water-soluble complex of any one of claims 1-15, wherein the water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

22. The water-soluble complex of any one of claims 1-15, wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours.

23. The dried form of the water-soluble complex of any one of claims 1-20, wherein the water-soluble complex is stable at 30 °C for at least 90 days when dried.

24. The water-soluble complex of any one of claims 1-20, wherein the water-soluble complex is formulated as a powder, tablet, orally disintegrating tablet, capsule, liquid, gel, film, lozenge, effervescent powder or tablet, emulsion, or for parenteral administration.

25. The water-soluble complex of claim 24, wherein the water-soluble complex is formulated for application via intradermal, subcutaneous, intramuscular, intraperitoneal, intrathecal, intravenous, topical (e.g., gel, emulsion, spray, or inhalation form) or as a transdermal patch.

26. The water-soluble complex of any one of claims 1-22 and 24-25, wherein the water-soluble complex is in the form of a film, effervescent powder or tablet, syrup, solution, elixir, emulsion, chewing gum, lollipop, sublingual drops, soft gel or tincture.

27. A water-soluble complex comprising non-nutritive sugars and pharmaceutical compounds, the water-soluble complex comprising: The molar ratio of approximately 1 to 12 moles of non-nutritive sugars per mole of the drug compound, wherein the non-nutritive sugars are one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitin B, dodecyl-β-D-maltodextrin, coixol, or eugenol A; The water-soluble complex is stable in water for at least 2 hours at pH 8.5 and / or pH 4.0, respectively. The conditions are that the water-soluble complex has at least a two (2)-fold increase in water solubility at 20 °C compared to the water solubility of the drug compound not in the water-soluble complex, and / or at least one improved pharmacokinetic property; and Furthermore, the condition is that the non-nutritive sugars in the daily unit dose of this water-soluble complex do not exceed approximately 280 mg. The pharmaceutical compound is used to lower blood glucose and / or blood A1C in a subject, and is insulin, an insulin analog, a natural insulin variant, a GLP-1 receptor agonist, an incretin mimic, a GIP agonist, an amylin agonist, a glucagon agonist, or a salt thereof.

28. A method for preparing a water-soluble complex, said water-soluble complex comprising a non-nutritive sugar and a pharmaceutical compound, the method comprising the following steps: (a) Mixing one or more solvents, a non-nutritive sugar, and a pharmaceutical compound, wherein the molar ratio of the non-nutritive sugar to the pharmaceutical compound is about 1 to about 12 moles of non-nutritive sugar per mole of pharmaceutical compound, wherein the formation of a water-soluble complex can be determined by nuclear magnetic resonance spectroscopy (NMR), and wherein the non-nutritive sugar is one or more of ADVANTAME®, NEOTAME®, sematinine, saccharin, sucralose, monk fruit, aspartame, acesulfame potassium, allulose, raspberry glycoside, dulcitidine B, dodecyl-β-D-maltose glycoside, coixol, or neohesperidin A; and wherein the mixing step is optionally carried out with a pharmaceutically acceptable acid and / or a nonionic surfactant; and (b) Drying the water-soluble complex and dissolving the water-soluble complex in water; and The pharmaceutical compound is used to lower blood glucose and / or blood A1C in a subject, and is insulin, an insulin analog, a natural insulin variant, a GLP-1 receptor agonist, an incretin mimic, a GIP agonist, an amylin agonist, a glucagon agonist, or a salt thereof.

29. The method of claim 28, wherein the method further comprises adding a nonionic surfactant to the solvent of step a).

30. The method of claim 28, wherein the pharmaceutical compound is rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, or ultra-long-acting insulin.

31. The method of claim 28, wherein the pharmaceutical compound is an insulin analog, natural insulin, or an insulin variant.

32. The method of claim 31, wherein the insulin analogue is lispro insulin, aspart insulin, glutathione insulin, admelog insulin, NPH insulin, protamine zinc insulin, glargine insulin, detemir insulin, or degludec insulin.

33. The method of claim 28, wherein the pharmaceutical compound is a GLP-1 receptor agonist.

34. The method of claim 33, wherein the GLP-1 receptor agonist is semaglutide, telposide, amiklipine, oxaliplatin, abiglutide, benaglutide, caglionetin, CagriSema, CT996, dapagliflozin, efenoxetine, HM15211, liximab, peptidoglycan, retaglutide, SCO-094, sovoglutide, WK2735, mascara, PEG-profenatide (PEX168), liraglutide, dulaglutide, ezenatide, or a salt thereof.

35. The method of claim 28, wherein the pharmaceutical compound is a GIP agonist.

36. The method of claim 35, wherein the GIP agonist is HM15211, rapaglutide, SCO-094, telpoglycinide, WK2735, or ZP6590.

37. The method of claim 28, wherein the pharmaceutical compound is a glucagon agonist.

38. The method of claim 37, wherein the glucagon agonist is affinoside, HM15211, mascara, pevitide, or sovorutide.

39. The method of claim 28, wherein the pharmaceutical compound is an amylin agonist.

40. The method of claim 39, wherein the amylin agonist is AZD6234, caglitinide, CagriSema, CT388, a long-acting amylin agonist, amiklipine, or ZP8396.

41. The method of claim 28, wherein the method further comprises drying the dissolved water-soluble complex in step b).

42. The method of claim 41, wherein the dried water-soluble complex is redissolved in a liquid.

43. The method of claim 28, wherein step a) comprises a sufficient amount of the pharmaceutically acceptable acid to dissolve the reaction mixture and to homogenize and clarify the reaction mixture.

44. The method of claim 43, wherein the pharmaceutically acceptable acid is acetic acid, ascorbic acid, aspartic acid, citric acid, formic acid, fumaric acid, gluconic acid, glutamic acid, glutamate, glycolic acid, hydrochloric acid, lactic acid, lauric acid, maleic acid, malic acid, malonic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, propionic acid, salicylic acid, stearic acid, succinic acid, or tartaric acid.

45. The method of claim 28, wherein the water-soluble complex comprises a molar ratio of about 1 to about 10 moles of non-nutritive sugars per mole of pharmaceutical compound.

46. ​​The method of claim 45, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

47. The method of claim 45, wherein the water-soluble complex comprises a molar ratio of about 2 to about 5 moles of non-nutritive sugars per mole of pharmaceutical compound.

48. The method of claim 47, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

49. The method of claim 45, wherein the water-soluble complex comprises a molar ratio of about 2 to about 4.5 moles of non-nutritive sugars per mole of pharmaceutical compound.

50. The method of claim 49, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

51. The method of claim 45, wherein the water-soluble complex comprises a molar ratio of about 8 moles of non-nutritive sugars per mole of pharmaceutical compound.

52. The method of claim 51, wherein the non-nutritive sugar is raspberry glycoside or carabinin.

53. The method of claim 28, wherein the water-soluble complex is stable in water at pH 8.5 for at least 2 hours.

54. The method of claim 28, wherein the water-soluble complex is stable in water at pH 4 for at least 2 hours.

55. The method of claim 28 further includes drying the water-soluble complex, comprising freeze-drying or lyophilization.

56. The method of claim 55, wherein the dried water-soluble complex is formulated in a pill or a pharmaceutically acceptable liquid.

57. A method for treating a subject with type 1 diabetes (TD1), type 2 diabetes (TD2), obesity (weight loss), MASH (metabolic steatohepatitis), glycemic control, prediabetes, a condition characterized by impaired fasting glucose or impaired glucose tolerance, α- and β-cell dysfunction, and / or a condition with suboptimal incretin effect, the method comprising administering to the subject a therapeutically effective amount of the water-soluble complex of any one of claims 1-27.

58. Use of the water-soluble complex of any one of claims 1-27 in the preparation of a medicament for treating type 1 diabetes (TD1), type 2 diabetes (TD2), obesity (weight loss), MASH (metabolic steatohepatitis), glycemic control, prediabetes, conditions characterized by impaired fasting glucose or impaired glucose tolerance, α- and β-cell dysfunction, and / or conditions with suboptimal incretin effects.

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