Background/Objectives: This study investigates the use of natural deep eutectic solvents (NADESs) in enhancing the solubility and skin permeation of a lidocaine base, a lipophilic form, in hydrogel systems. The aim was to develop an environmentally sustainable and biocompatible alternative to conventional lidocaine formulations, improving the dermal permeation and therapeutic efficacy. Methods: The lidocaine base was dissolved in a hydrophilic NADES system composed of choline chloride and citric acid, facilitating enhanced solubility, likely through new molecular interactions. Then, pH-adjusted hydrogels were formulated and optimized by employing a 3² full factorial design. Raman and nuclear magnetic resonance (NMR) spectroscopy were applied to evaluate the stability of lidocaine in the optimal formulation. The biopharmaceutical properties were investigated using in vitro drug release and skin permeation studies. In vivo tests assessed physiological skin parameters such as the hydration and transepidermal water loss. Results: The developed NADES-containing hydrogel significantly improved the solubility and stability of lidocaine. Skin permeation studies demonstrated enhanced dermal permeation compared with conventional hydrogel and ointment. These improvements, namely the enhanced solubility of lidocaine in the formulation and its increased permeation, were attributed to the dual effect of the NADES. Conclusions: NADES-containing hydrogels represent a promising green technology for formulating lidocaine-containing dermal preparations. This approach offers a biocompatible, natural-based alternative that can enhance the bioavailability and efficacy of topical anesthetics.

Background: Additive manufacturing provides a rapid and flexible alternative to conventional micromolding for producing microneedle systems. This study evaluates the potential of a cost-effective LCD 3D printer for fabricating microneedle arrays (MNAs) and investigates how the geometry of MNAs and the formulation of hydrogel influence the performance of lidocaine-coated arrays. Methods: Conical and pyramidal MNAs, along with a reservoir plate, were designed and manufactured. Lidocaine-loaded and placebo hydrogels with two different polymer concentrations were prepared for dip-coating using both single and multilayer applications. Mechanical resistance and insertion efficiency were evaluated under controlled compression. The physicochemical behavior of the hydrogels were characterized, including pH, spreadability, adhesiveness, and rheological behavior. The uniformity of the coating was analyzed using 3D confocal microscopy. Drug loading was quantified by HPLC, drug release was studied using Franz diffusion cells, and skin penetration was confirmed by 3D confocal imaging and Raman mapping. Results: Conical microneedles exhibited high mechanical integrity, showing only a 2% reduction in height compared to 4% for pyramidal MNAs. Stronger drug signals were achieved in deeper skin layers with the conical geometry, indicating enhanced penetration, while pyramidal MNAs provided slightly higher lidocaine loading due to their larger lateral surface. Hydrogels with higher polymer content produced more stable, uniform coatings, particularly when applied in three layers. Rapid drug release was observed, with over 70% of the drug delivered within minutes. Conclusions: LCD 3D printing offers a cost-effective approach for fabricating MNAs with suitable structural stability and sharpness. The optimized hydrogel formulation ensured uniform coverage, as well as maximal and consistence penetration, making this platform a promising candidate for the dermal delivery of other potent drugs.