Design of Nonsteroidal Anti-Inflammatory Drug-Based Ionic Liquids with Improved Water Solubility and Drug Delivery

Abstract

We here report the synthesis of ionic liquids (ILs) composed of the cholinium cation and anions derived from nonsteroidal anti-inflammatory drugs (NSAIDs), namely ibuprofen, ketoprofen, and (S)-naproxen, and their incorporation into bacterial nanocellulose envisaging their use in topical drug delivery systems. The chemical structure of the synthesized ILs was confirmed by spectroscopic techniques, and thermal analysis confirming their categorization as ionic liquids with melting temperatures below 100 °C and resistance to autoclaving. The synthesized ILs display an aqueous solubility (at pH 7.4) ranging between 120 and 360 mM, which is up to 100 times higher than the solubility of the respective NSAID precursors, thus contributing to improved bioavailability. Their incorporation into bacterial cellulose originated transparent and homogeneous membranes. Thermogravimetric analysis (stable up to at least 225 °C) and mechanical assays (with minimum Young’s modulus of 937 MPa, maximum stress of 33 MPa and elongation at break of 5.6%) confirmed the suitability of the prepared membranes for application as topical drug delivery systems. Furthermore, the rehydration ability of IL-incorporated membranes is 18 to 26 times higher than bacterial cellulose, being valuable to the absorption of exudates. Release tests demonstrated a faster and complete release of the IL-based drugs when compared with the starting NSAIDs. Finally, it is demonstrated that bacterial cellulose is not cytotoxic nor proinflammatory, whereas the cytotoxicity and anti-inflammatory properties of IL-incorporated BC membranes are similar to those of NSAIDs or ILs, reinforcing their suitability as envisioned materials for topical drug release applications.

Nanocellulose-Based Patches Loaded with Hyaluronic Acid and Diclofenac towards Aphthous Stomatitis Treatment

“…According to the data provided in Figure 7a, the HaCaT cells' metabolic activity after 24 h of exposure to BNC membrane (93±5% cell viability) is similar to that of the negative control (100% cell viability). Hence, the BNC membrane is non-cytotoxic to HaCaT cells, which is consistent with the results obtained in literature for this cell line [28,31], but also for other cell lines, e.g., RAW 264.7 cells [55] and adipose-derived stem cells (ADSCs) [56]. Figure 7a, the HaCaT cells' metabolic activity after 24 h of exposure to BNC membrane (93±5% cell viability) is similar to that of the negative control (100% cell viability).…”

Functional biohybrid materials based on halloysite, sepiolite and cellulose nanofibers for health applications

“…In this case, once the drugs are released from the lumen, the interactions with the other matrix components are important and determine the release kinetics. For instance, strong interactions have been reported to exist between IBU and the nanocellulose, 76 which could explain the slower IBU release kinetics from the HNT-SEP-CNF hybrid nanopaper as compared to SA. In addition, the openings of the nanotubes could be partially obstructed by the particular texture of the film and thus, sustained the drug release.…”

Topical Drug Delivery Systems Based on Bacterial Nanocellulose: Accelerated Stability Testing

“…Several studies have confirmed that pure BNC membranes can be successfully loaded with multiple active pharmaceutical ingredients (APIs) (or other bioactive molecules) with different structures, solubility and hydrophilicity. For instance, neat BNC membranes have already been combined with drugs and other bioactive compounds, such as lidocaine [22,23], ibuprofen [23], caffeine [24], diclofenac [25] and amoxicillin [26] in their most common forms or formulated as ionic liquids [27,28] for cutaneous drug delivery. There are also examples of BNC-based nanocomposites being used for the cutaneous delivery of diclofenac [29] and BNC-based hybrid films for the cutaneous delivery of levofloxacin [30].…”