# Diversity of Potential (Bio)Technological Applications of Amino Acid-Based Ionic Liquids
## 2 Bioapplications of AA ILs: An Overview  
### Drug Formulations and Delivery  
The conversion of active pharmaceutical ingredients (APIs) into ILs is a widely studied strategy to improve water solubility and long-term stability, prevent polymorphism, modify pharmacokinetic profiles, or suggest new routes of administration for orally administered drugs. AAs are biocompatible, and their ILs, in which the API serves as either a cation or anion, have been the focus of recent studies [38; 39; 40; 41]. The most studied ILs contain AA ester cations paired with non-steroidal anti-inflammatory drug (NSAID) anions such as ibuprofen (Ibu), naproxen (Nap), ketoprofen (Keto), and salicylic acid (SA). Novel topical and transdermal formulations are being developed to minimize the gastrointestinal mucosal damage caused by orally administered NSAIDs, especially at high doses or during prolonged use [42]. Numerous in vitro studies using porcine skin models have demonstrated the penetration-enhancing properties of AA ILs. For example, [ProOEt][Ibu] showed a 10-fold increase in the cumulative drug amount at 96 h compared to the acid form of Ibu [43]. Notably, ProOEt is a compatible cation, and at a concentration of 50 mM, it reduced murine fibroblast viability by only 20% [43]. In addition, a large series of ILs containing isopropyl (i-Pr) esters of AAs and Ibu showed 6- to 120-fold increases in solubility in water and PBS, as well as more than a 16-fold increase in cumulative permeation through a model skin system [44]. As expected, an increase in lipophilicity and skin permeability was observed for a series of L-Glu alkyl ester Ibu salts, with permeability correlating with the increase in alkyl chain length from ethyl to pentyl [45]. These compounds show good potential for transdermal delivery systems of Ibu. Conversely, within a short series of Pro short alkyl AA ester naproxenates, the isopropyl ester exhibited the highest permeability in a porcine skin model [46]. [PERSON] et al. demonstrated that [AAOEt][SA] penetrated more than nine times faster than the sodium salt. The best transport behavior was observed for [Asp][SA], followed by [Ala][SA], and then [ProOEt][SA] [27]. ILs composed of Et esters of hydrophobic amino acids (L-Ala, L-Pro, and L-Leu) as cations and free fatty acids (oleic or linoleic) as anions have been proposed as drug delivery systems for Ibu or the model peptide drug ovalbumin epitope [47]. These ILs demonstrated good miscibility with solvents such as isopropyl myristate and DMSO, as well as with emulsifiers such as Span-20, which are commonly used in formulations. Additionally, they showed no toxic effects in a reconstructed human epidermal model assay. In vitro, a formulation containing 10% [ProOEt][linoleate] in isopropyl myristate was found to enhance the skin permeation of Ibu or ovalbumin more effectively than sodium lauryl sulfate, a conventional chemical permeation enhancer [47]. Extensive research has shown that AA alkyl ester hydrochlorides are excellent chemical skin penetration enhancers. For a large series of AAOMe hydrochloride, with the exception of [ValOMe][Cl], [PERSON] et al. reported a similar or improved ability to facilitate the transport of 5-fluorouracil or hydrocortisone across a skin model compared to Tween 20, Azone(r), or Transcutol(r)[48]. Increasing the alkyl chain length of the ester substituent to octanoyl (Oct) or lauryl (Lau) resulted in up to a 6-fold and 2-fold improvement in skin permeation parameters (flux rate for 5-fluorouracilacil and hydrocortisone, respectively). A clear dependence on the chain length of the ester was observed. Among the two drugs, [LeuOLau][Cl] showed the highest potential as a skin permeation enhancer and exhibited low toxicity to fibroblasts (IC\({}_{50}\) = 387 uM) and keratinocytes (IC\({}_{50}\) = 177 uM) [48]. In addition to developing new topical drug formulations, the IL strategy can also be used to improve the pharmacokinetic properties of oral drug formulations. In a clinical trial, [PERSON] et al.