# Has the Toxicity of Therapeutic Deep Eutectic Systems
###### Abstract  
Therapeutic Deep Eutectic Systems (THEDESs) are a mixture of components, including an active pharmaceutical ingredient, that have recently emerged because of their interesting properties for drug therapies. In general, they have been recognized to increase the solubility and permeability of some drugs, and consequently, their bioavailability. Moreover, they have also been used for novel formulations of pharmaceuticals. Despite the potential benefits of THEDESs, concerns about their safety and toxicity remain. In this review, we summarize previous studies that have investigated the toxicity of THEDESs. These studies evaluate the toxicity of THEDESs using various methods, including cell cultures, animal models, and human trials. The results of previous findings suggest that THEDESs are generally well-tolerated and have low toxicity. However, further research is needed to fully understand the long-term effects of these systems on human health and to identify any potential adverse effects. eutectic; cytotoxicity; cell viability; gene expression; animal models; human therapeutics +
Footnote †: journal: Medical  
bond donor (HBD), which, at a particular molar composition, become liquid at room temperature. Their liquefaction is reached only by the interaction between their components, not involving any chemical reaction. However, the stability of DESs is a crucial factor that must be considered when evaluating their potential uses, and it was found that the hydrogen bond plays an important role in its thermostability [14; 15]. As it can be possible to choose the components, they are usually non-toxic, biodegradable, and biocompatible molecules [16]. The most used components are chemicals such as sugars, alcohols, urea, natural metabolites, organic acids, and choline chloride (ChCl), among others [17; 18]. When one of these components is an active pharmaceutical ingredient (API), these systems are renamed THEDESs (Therapeutic Deep Eutectic Systems). The first THEDES was reported by [PERSON] and co-workers in 1998 by mixing ibuprofen as an API and seven skin penetration enhancers to obtain eutectic systems [19]. In a THEDES, an API can be served both as an HBA and HBD. For example, aspirin can be used as the hydrogen bond donor to form DES with ChCl [20], while lidocaine and atropine can be used as the hydrogen bond acceptor to construct DES with carboxylic acid [21]. They offer a wide range of advantages when combined. In several pharmaceutical fields, DESs have been useful in order to increase the drug solubility, permeation, and absorption [22]. Compounds such as paracetamol, aspirin, and salicylic acid are very poorly soluble in water. However, by using a DES as a solvent, for example, mixtures of urea, ChCl could dissolve benzoic acid, danazol and itraconazole [23]. [PERSON] et al. prepared different THEDESs based on menthol complexed with different APIs (ibuprofen, phenylacetic acid, and benzoic acid). The solubility and permeability of the systems in an isotonic solution was evaluated and compared with the pure APIs [24]. The authors concluded that with the exception of the system containing phenylacetic acid, for the rest of the mixtures, the solubility of the APIs when they are in the THEDES can be improved up to 12-fold, and the permeability can be improved up to 3-fold in comparison with the pure APIs. Therefore, this work demonstrates the efficiency of a THEDES as a new formulation in order to improve the bioavailability of APIs by changing the physical state of the molecules from a solid dosage to a liquid system. However, only a few studies study the combination of two APIs as counterparts to obtain a THEDES. This is the case of the paper published by [PERSON] et al., who constructed a new THEDES based on two APIs derived from natural products, osthelo and paeonol. Osthole has a wide variety of pharmacological functions, such as antimicrobial, antioxidant, and anticancer functions, and paeonol is known as a great anti-inflammatory, antioxidant, and antibacterial agent [25].