Pharmaceutical applications of therapeutic deep eutectic systems (THEDES) in maximising drug delivery.

The issue of poor solubility of active pharmaceutical ingredients (APIs) has been a salient area of investigation and novel drug delivery systems are being developed to improve the solubility of drugs, enhance their permeability and thereby their efficacy. Several techniques for solubilization enhancement of poorly soluble drugs are often employed at various stages of pharmaceutical drug product development. One such delivery system is the therapeutic deep eutectic system (THEDES), which showed great potential in the enhancement of solubility and permeability of drugs and ultimately augmenting their bioavailability. THEDES are made by mixing drugs with deep eutectic solvents (DESs) in a definite molar ratio by the hit and trial method. The DESs are a new class of green solvents which are non-toxic, cheap, easy to prepare, biodegradable and have multiple applications in the pharmaceutical industry. The terminologies such as ionic liquids (ILs), DES, THEDES, and therapeutic liquid eutectic systems (THELES) have been very much in use recently, and it is important to highlight the pharmaceutical applications of these unexplored reservoirs in drug solubilization enhancement, drug delivery routes, and in the management of various diseases. This review is aimed at discussing the components, formulation strategies, and routes of administration of THEDES that are used in developing the formulation. Also, the major pharmaceutical applications of THEDES in the treatment of various metabolic and non-metabolic diseases are reviewed.

Levofloxacin-Fatty Acid Systems: Dual Enhancement Through Deep Eutectic Formation and Solubilization for Pharmaceutical Potential and Antibacterial Activity.

Fatty acids, including medium-chain saturated and polyunsaturated fatty acids, are known for their broad health benefits, including antimicrobial activity. Through their green properties, deep eutectic systems have been heralded as having the potential to be at the forefront of pharmaceutical applications. In this work, capric acid and geranic acid, two examples of medium-chain saturated and polyunsaturated fatty acids, were employed to enhance the pharmaceutical properties and the antibacterial activity of levofloxacin. To this end, levofloxacin formulations with either capric or geranic acid were prepared and characterized using appropriate techniques. Levofloxacin was utilized to create innovative deep eutectic systems in conjunction with capric acid at three different molar ratios: 1:9, 2:8 and 3:7. This was confirmed through a rigorous analysis involving nuclear magnetic resonance, infrared spectroscopy and differential scanning calorimetry. Furthermore, it is noteworthy that geranic acid demonstrated an impressive threefold improvement in levofloxacin's solubility compared to its solubility in aqueous solutions. The antibacterial activity of the novel combinations of levofloxacin with either fatty acid was evaluated using a checkerboard titration assay. Gratifyingly, both formulations exhibited synergistic effects against a panel of levofloxacin-sensitive and resistant Gram-negative bacteria. In conclusion, the observed superior antibacterial activity of levofloxacin illuminates the potential use of fatty acid-based formulations and deep eutectic systems as green and innovative strategies to combat the global antimicrobial resistance problem.

Preparation of carbon-rich material from Dendrobium officinale polysaccharide in deep eutectic system.

A carbon-rich material (DESysChar) was prepared from polysaccharide within a deep eutectic system (DESys) containing oxalic acid, and systematically characterized using various analytical techniques. The investigation of reaction mechanism revealed concurrent dehydration and etherification processes. This study commenced with the extraction of plant polysaccharide using the DESys-based mechanochemical extraction method from Dendrobium officinale. Subsequently, the DESys method was used to carbonize the extracted Dendrobium officinale polysaccharide and produce DESysChar. DESysChar was then used for the adsorption and determination of pollutants in water. This study represents a significant advancement in eco-friendly material synthesis, enabling the low-temperature (120 °C) carbonization of plant-derived polysaccharides, thereby reducing energy consumption and environmental impact. The effective adsorption of methylene blue by DESysChar underscores its potential in environmental remediation. This study presents a more responsible and efficient approach to polysaccharide extraction and carbonization, addressing environmental concerns. Embracing the 4S workflow (involving Sustainable raw materials converted into Sustainable degradable products, by using Sustainable technology throughout the process to create a Sustainable environment) promotes sustainability in material development, laying the foundation for future eco-friendly practices in various industries. In summary, this study propels sustainable polysaccharide development for widespread use.

Effect of Deep Eutectic System (DES) on Oral Bioavailability of Celecoxib: In Silico, In Vitro, and In Vivo Study.

Different deep eutectic systems (DES) of choline chloride (CC)-urea (UA) (1:2), CC-glycerol (GLY) (1:2), CC-malonic acid (MA) (1:1), and CC-ascorbic acid (AA) (2:1) were generated and characterized by polarized light microscope (PLM) and Fourier transform infrared spectroscope (FTIR). The equilibrium solubility of celecoxib (CLX) in DES was compared to that in deionized water. The CC-MA (1:1) system provided ~10,000 times improvement in the solubility of CLX (13,114.75 µg/g) and was used for the generation of the CLX-DES system. The latter was characterized by PLM and FTIR to study the microstructure and intermolecular interaction between the CLX and CC-MA (1:1) DES. FTIR demonstrated the retention of the chemical structure of CLX. In vitro drug release studies in FaSSIF initially demonstrated high supersaturation, which decreased by ~2 fold after 2 h. Density functional theory (DFT)-based calculations provided a molecular-level understanding of enhanced solubility. Gibbs free energy calculations established the role of the strongest binding of CLX with CC and MA. A phase solubility study highlighted the role of hydrotropy-induced solubilization of the CLX-DES system. Animal pharmacokinetic studies established 2.76 times improvement in Cmax, 1.52 times reduction in tmax, and 1.81 times improvement in AUC0-∞. The overall results demonstrated the potential of developing a DES-based supersaturating drug-delivery system for pharmaceutical loading of drugs having solubility and dissolution rate-limited oral bioavailability.

Ionic liquid as hydrogen bond acceptor in the extraction of nutritional natural products.

In-depth studies of the extraction mechanism using deep eutectic solvents (DES), especially extraction through the formation of a deep eutectic system (DESys), revealed commonalities between the DES- and ionic liquids (IL)-based extraction systems. New applications of ILs and DES for extraction of nutritional natural products were presented. In this study, the extraction behavior of choline chloride (ChCl) and 1-(2-hydroxyethyl)-3-methylimidazolium chloride ([HMIm][Cl]) in DES and IL, respectively, in mechanochemical extraction of target compounds from Moringa oleifera leaves was systematically studied. The results suggested that both extraction methods were based on the formation of a DESys, either a normal DESys or an IL DESys. Considering the DESys-based one-step extraction improves the extraction efficiency and reduces the preparation time, the same idea can be used in IL for performance improvement. By formation of a new IL deep eutectic system based on hydrogen bond interaction in extraction, similar improvement was obtained.

Plant polysaccharide itself as hydrogen bond donor in a deep eutectic system-based mechanochemical extraction method.

A deep eutectic system (DESys) is formed when a hydrogen bond acceptor (HBA) is processed with polysaccharide (hydrogen bond donor, HBD) containing plant substance in water to dissolve, extract, and recover the polysaccharide directly, instead of using a traditional deep eutectic solvent (DES). The extraction efficiency is enhanced by the direct formation of the DESys, in a mechanochemical extraction (MCE) system. Key factors affecting the extraction efficiency were systematically studied and optimized. The effects of the DESys on the structure and physicochemical properties of polysaccharides were studied by several analytical techniques. The findings demonstrated that the direct DESys formation extraction efficiency was superior than that of traditional extraction methods while retaining physicochemical properties of polysaccharides. Moreover, the composition of polysaccharides extracted with this method is different from that obtained by conventional methods. The recovery and purification process of polysaccharides is simplified by eliminating the need for an additional HBD.

Deep eutectic systems: An overview of fundamental aspects, current understanding and drug delivery applications.

The deep eutectic system (DES) is a relatively new concept in the field of drug delivery science. DES is a class of eutectic mixtures comprised of two or more components, with a eutectic point far below than the melting temperature of the pure components. The strong hydrogen bonding interactions between DES constituents are responsible for significant lowering of melting point in DES. A significant number of molecules cannot reach from drug discovery phase to drug development phase because of poor biopharmaceutical attributes, such as solubility and permeability. DES can be a novel alternative to overcome these issues. In last few years DESs have been widely used in different pharmaceutical and chemical processes. However, comprehensive information regarding their drug delivery potential is not available. This review deals with fundamental aspects such as types, preparation, thermodynamics, toxicity, biodegradability and their applications in the field of drug delivery. Current challenges, future prospects and translational aspects of DES as drug delivery system have also been discussed.