Water-insoluble drugs and functional-food components are difficult to formulate in liquid form and are poorly bioavailable as a consequence; hence, solubilization is an important drug-development theme. Herein, we report our research efforts toward improving the solubilities of water-insoluble compounds using functional-polymer-based drug-delivery systems (DDSs) with the aim of expanding both effectiveness and applicability. As part of this study, we developed polyethylene-glycol-monostearate-based nanomicelle formulations for resveratrol and coenzyme Q10 as functional-food components. We also developed hyaluronic-acid- and polyvinyl-alcohol-based eye-drop formulations, as well as styrene-maleic-acid-copolymer-based intravenous formulations for amphotericin B, an antifungal drug. These formulations led to improved drug solubility and safety. This article introduces polymer-based DDSs as effective platform technologies that enable the solubilization of water-insoluble compounds.

Ionic liquids (ILs) have emerged as alternative solvents with unique solubilization abilities distinct from those of water and conventional organic solvents. However, most ILs were not originally developed for biological applications, leading to concerns about their toxicity and safety. To overcome these limitations, biocompatible ionic liquids (Biocompatible ILs) composed of naturally derived components such as choline and amino acids have recently attracted considerable interest in pharmaceutical field. This review summarizes recent advances in Biocompatible ILs, including choline–geranate (CAGE), amino acid–fatty acid ILs, and choline–amino acid ILs, with a focus on their ability to enhance the solubility of poorly water-soluble active pharmaceutical ingredients (APIs) and the mechanisms underlying solubilization. Such Biocompatible ILs hold promise for improving the oral absorption, skin permeability, and overall bioavailability of APIs.

For poorly soluble compounds, the dissolution process often becomes the rate-limiting step in oral absorption; therefore, improving solubility is crucial for enhancing the bioavailability of such compounds. Transglycosylated compounds are derivatives obtained by enzymatic modification to parent compounds, in which a sugar moiety is added. An interesting feature of these compounds is that the addition of just one sugar molecule to the parent compound can dramatically increase its solubility. Investigation into the mechanism underlying this remarkable enhancement revealed that enzyme-treated compounds form molecular aggregates in aqueous solution, and poorly soluble compounds can be solubilized in that structures. Furthermore, it was found that the structure of these molecular aggregates differs depending on the type of transglycosylated compounds. In this study, we introduce the solubility and oral absorption-enhancing effects of four transglycosylated compounds: transglycosylated hesperidin, transglycosylated rutin, transglycosylated stevia, and transglycosylated naringin.

Cyclodextrins (CDs) are cyclic oligosaccharides consisting of (α-1,4)-linked D-glucopyranose units. In aqueous solutions, CDs form water-soluble inclusion complexes with poorly soluble lipophilic compounds via uptake of some of the lipophilic moieties of the compounds into the central cavity. As lipophilic compounds form complexes with CDs through non-covalent intermolecular interactions, the formation of inclusion complexes between CDs and lipophilic compounds in solution is in an equilibrium state. Although CDs are widely used to solubilize poorly soluble drugs, they rarely penetrate biological membranes under physiological conditions, enabling only the drug released from the CD to be absorbed through the membrane. While the formation of strong inclusion complexes in aqueous solution promotes drug solubilization, the drug must be released from the CD for absorption into the body. Therefore, when using CDs for drug solubilization, it is important to consider the stability constant between the drug and the chosen CD. Even though recent advances in high-throughput technology have facilitated the development of many new and potentially useful compounds, a large proportion are poorly soluble in water. Maximizing the capabilities of CDs should thus enable the use of many new but poorly soluble compounds as pharmaceuticals or for other applications.