(556b) Formulation and Screening of NSAID Ionic Liquids for Transdermal Delivery

Transdermal drug delivery is a safe, painless, and noninvasive alternative to hypodermic injections and oral delivery for drug administration. This route can help circumvent first-pass hepatic elimination while being both inexpensive and self-administrable, making it more attractive than traditional routes of delivery while improving patient compliance. The main challenge, however, is overcoming transport limitations across the uppermost barrier of the skin, the stratum corneum, a tightly packed structure that allows only for a few drugs possessing low mass and high lipophilicity to pass without assistance.

Ionic liquids (ILs), which are organic salts that remain liquid below temperatures of 100℃, have the potential to address limitations of transdermal drug delivery through several unique properties in addition to strong interactions among their constituent ions. Their utility in pharmaceutical research has already addressed several challenges of poor drug solubility, thermal stability, and bioavailability of traditional drugs. Thus, the transdermal route is an attractive new frontier where ILs can be leveraged.

In this presentation we highlight the development and screening of a set of 18 prospective ILs to identify candidates most suitable for transdermal delivery through a series of in vitro and in vivo experiments. Prior work helped screen a combination of 6 non-steroidal anti-inflammatory drugs (NSAIDs) paired with 10 counterions molecules of varying size and chemical properties to identify 18 IL drug candidates selected for their ability to form room temperature ILs.

Aqueous solubility and distribution coefficient experiments helped us refine our list of prospective candidates to those that possess both high aqueous solubility and high octanol-water distribution coefficient, which are indicative of favorable mass flux and permeability properties. Mass flux and permeability of each IL were then determined ex vivo via a Franz Cell apparatus using porcine skin.

The permeability study found that NSAIDs paired with a triethylamine counterion yielded the most suitable ionic liquids for transdermal delivery with mass flux enhancements up to ~40-fold greater than other ILs with the same NSAID and different counterion. While NSAID-benzethonium ILs demonstrated the highest distribution coefficient and aqueous solubility of all counterions followed by triethylamine ILs, the former performed poorer in permeability experiments than the latter. We theorize that benzethonium’s bulkiness contributed to its transport limitations across the skin as it was the largest of counterions paired with NSAID ions and was four times larger than triethylamine by molecular weight.

This study demonstrates that NSAID ILs possess properties that can enhance transdermal delivery and that the better performing candidates were those with high aqueous solubility, high distribution coefficient and low molecular weight. On-going work done in vivo will help further confirm these observations while helping us understand the structural properties that dictate a molecule’s ability to permeate through the skin.