Exploring innovative drug delivery approaches through the use of Deep Eutectic Solvent

In pharmaceutical sciences, developing advanced drug delivery systems (DDS) is essential to overcome therapeutic limitations associated with poor solubility, bioavailability, and stability of active ingredients. Deep eutectic solvents (DES) have emerged as promising solutions due to their unique properties, making them a versatile and beneficial platform for enhancing the formulation, solubility, and stability of active pharmaceutical ingredients (APIs). This doctoral research examines the physicochemical characteristics of DES, highlighting their potential application in DDS, particularly for APIs with low aqueous solubility. This study leverages DES to address solubility and permeability challenges across different drug classes classified according to the Biopharmaceutical Classification System (BCS). A noteworthy example of DES application and designed by nature itself is honey, which serves as a case study for its natural eutectic properties, demonstrating the potential of DES to improve the solubility, stability, and biopharmaceutical performance of the specific compounds that give honey its properties. Special attention is given to the molecular mechanisms governing DES formation and functionality, such as the physicochemical properties and hydrogen bond interactions responsible for the drastic reduction in melting point. This research aims to demonstrate how DES, due to their versatility and adaptability, can be tailored to meet the specific needs of pharmaceutical delivery. An innovative aspect of this research is the application of cyclodextrin-based supramolecular DES (CycloDES) to improve the solubility of poorly water-soluble drugs such as cannabidiol (CBD), dexamethasone, and indomethacin. The CycloDES system utilizes modified cyclodextrins to form hydrogen bonds, optimizing solubility (with improvements of at least 100 times compared to aqueous solubility) and permeability of the studied compounds without the need for additional solvents. It also preserves the drugs in solution upon dilution to a greater extent than a glucose and choline chloride-based DES model. Additionally, therapeutic eutectic solvents (THEDES) were subsequently developed within self-emulsifying drug delivery systems (SEDDS) to enhance the bioavailability and stability of orally administered CBD. The resulting nanoemulsion not only facilitates passage through the stomach, maintaining the drug’s chemical stability but also increases CBD permeability across a CaCO-2 cell monolayer, a model for the intestinal epithelium, by 1,000 times. This THEDES-SEDDS approach demonstrates the compatibility and stability of DES in self-emulsifying formulations, with promising potential for large-scale pharmaceutical applications. Finally, to overcome the mucosal barrier encountered in oral drug administration, this research also explores the potential of developing mucolytic DES synthesized with N-acetylcysteine (NAC) and L-arginine. These DES utilize the thiol group of NAC to break disulfide bonds in mucin, facilitating drug transport across various mucin and mucus layers, with biocompatibility ensured through the use of compounds generally recognized as safe (GRAS). The resulting DES exhibit significant mucolytic potential, permeating the deeper layers of a mucopermeation analysis system and demonstrating that the DES approach enhances both the solubility of the model drug and NAC itself. Through a robust experimental approach, this thesis establishes DES as a promising, adaptable class of solvents for improving API delivery across a range of pharmaceutical applications, with implications for enhancing stability, efficacy, and therapeutic outcomes. The results underscore the adaptability of DES and their potential to drive innovation in pharmaceutical formulations.

Nelle scienze farmaceutiche, lo sviluppo di sistemi avanzati per il drug delivery (DDS) è essenziale per superare le limitazioni terapeutiche legate alla bassa solubilità, biodisponibilità e stabilità dei principi attivi. I deep eutectic solvent (DES) sono sistemi eutettici che si stanno affermando come una piattaforma innovativa e versatile per migliorare la solubilità, la stabilità e la formulazione degli API. Questa ricerca di dottorato analizza le proprietà chimico-fisiche dei DES, con particolare attenzione alla loro applicazione nei DDS, in particolare per API a bassa solubilità acquosa. Lo studio esplora l’impiego di DES in diverse formulazioni, dimostrando il potenziale di questi sistemi nel migliorare le propietà biofarmaceutiche dei farmaci modello. Tra le innovazioni, i sistemi CycloDES, DES includenti ciclodestrine nella loro composizione, hanno mostrato significativi miglioramenti di solubilità per farmaci lipofili (cannabidiolo, desametasone, indometacina). Un DES terapeutici (THEDES) con cannabidiolo, formulato in sistemi auto-emulsionanti (SEDDS), ha dimostrato di incrementare di 1000 volte la permeazione del cannabidiolo attraverso un modello di epitelio intestinale. Inoltre, sono stati sviluppati DES mucolitici a base di N-acetil cisteina e L-arginina, capaci di migliorare la permeabilità attraverso le barriere mucosali, mantenendo elevata biocompatibilità. Questo lavoro mette in evidenza come i DES possano essere modulati per soddisfare esigenze specifiche della somministrazione farmaceutica, con implicazioni e potenzialità significative per la stabilità, l’efficacia e il miglioramento degli esiti terapeutici, confermando il loro ruolo come classe promettente di solventi innovativi nelle formulazioni farmaceutiche.