(T1530-03-18) Physicochemical Characterization and In Vitro/Ex Vivo Evaluation of Transdermal Gels of Baricitinib for Rheumatoid Arthritis

Purpose: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint damage and disability, driven by inflammation-induced cartilage and bone destruction mediated by cytokines. In clinical studies, Baricitinib (BCB), a Janus kinase (JAK) inhibitor, has effectively reduced disease activity and inhibited joint damage progression. Despite its effectiveness, oral administration of BCB is associated with risks such as infections, cardiovascular events, cancer, and gastrointestinal issues, and hence comes with a black box warning. Transdermal drug delivery (TDD) presents a promising alternative, circumventing oral administration drawbacks. TDDS offers a route that avoids first-pass effects, reduces gastrointestinal side effects, and enhances overall bioavailability, thus improving patient compliance. Although BCB is classified as a BCS class II drug, it presents practical challenges due to its solubility and permeability issues, making formulating it into a gel a difficult task. To address this issue, a unique deep eutectic solvent known as Choline Geranic acid (CAGE), renowned for its exceptional solubilizing and permeation enhancing properties was employed effectively resolving formulation requirements. The current study aims to develop transdermal BCB gel formulations for enhanced local efficacy while minimizing systemic adverse effects. This is achieved through the controlled release of low drug concentrations at the application site, thus reducing systemic absorption while maintaining therapeutic concentration. The skin, our body's largest and most intricate organ, comprises layers with varying lipophilic and hydrophilic characteristics. Consequently, the passage of molecules through the skin into the bloodstream is a slow and intricate process, attributable to the diverse barriers inherent in the skin's structure. In this study, three distinct types of materials were used to formulate the gels. These comprised of polymeric (Hyaluronic acid, HA), lipid (Compritol), and protein (Lactoferrin, Lf) delivery systems. Hyaluronic acid (HA) has gained attention in rheumatology for its roles in joint lubrication and inflammation modulation; Compritol 888 ATO is valued for lipid nanoparticle formulation due to high drug entrapment and compatibility with hydrophilic and lipophilic drugs. Lactoferrin protein, a natural wound healer with anti-inflammatory properties is GRAS (Generally Regarded as Safe) by the USFDA, was explored due to its gelling capabilities. Either permeation enhancement or particle size reduction was employed as a strategy to augment the drug's penetration through the skin barrier.

Methods: Three distinct gel types of different strengths were formulated and characterized: HA gels, compritol gels, and Lf gels. The formulation of Ha and Lf gels involved the utilization of CAGE solvent. In the case of Lf gels, CAGE facilitated an enzymatic crosslinking reaction with tyramine to induce gel formation. Compritol, on the other hand, was employed to formulate lipid nanoparticles within an o/w emulsion, subsequently incorporated into Carbopol gel matrices. Various physicochemical characterization tests like FTIR, particle size analysis, zeta measurements, and imaging were performed to characterize gels. Rheological assessments, including amplitude, time, temperature, and frequency sweeps, were performed using an MCR 301 rheometer (Anton Paar) to characterize the gel properties. The IVRT and IVPT tests were conducted using a vertical Franz-Diffusion apparatus from PermeGear, employing cellulose and Strat M membranes for IVRT and porcine skin for IVPT. The temperature was maintained at 37±0.5 ºC, and the receiver fluid was optimized so that the maximum amount of release was obtained. A robust and sensitive HPLC method was developed for quantifying BCB. All the tests were performed in triplicates and represented as mean ± SD. Statistical tests were conducted to understand the difference in release and permeation profiles (ANOVA).

Results: The results showed different types of release and permeation kinetic profiles. Higuchi model kinetic permeation profile was best fitted for compritol and HA gels, whereas the Lf gels followed first-order kinetic permeation. The cumulative percent drug release from the optimized HA, Compritol, and Lf gels in cellulose membrane over 24 hours was 96.19±3.43, 78±2.3, and 83±4.2% respectively, and in Strat M membrane it was 65.11±2.59, 63±8.97, and 74±8.97% respectively. Cumulative amount permeated from these gels over 24 hours was 1.35 µg/cm², 0.88 µg/cm² and 2.54 µg/cm². Notably, drug release, permeation and flux was significantly higher in protein Lf gels in comparison to other gels. HA and Lf gels were found to be stable at 2-8 ºC whereas compritol gels were stable at room temperature for ~ 6 months.

Conclusion: Various transdermal gel formulations of BCB were developed and optimized based on IVRT and IVPT, which are considered as gold standard tests to study a transdermal product’s performance and quality. Among the three different types of formulations developed, HA gels depicted a better release profile using cellulose membrane, and Lf gels permeated better across Strat M® and porcine skin membranes. Based on the IVPT data the flux rate was calculated and LF gels were found to be more efficacious as transdermal gels. Based on these findings, Lf gels will be further taken up for pharmacokinetic studies in the animal model.


In vitro release test (IVRT) profiles of (A) Hyaluronic acid gels, (B) Compritol gels, (C) Lactoferrin gels. The studies were performed using synthetic cellulose membrane of 50kD mounted between the donor and receiver chambers of a vertical franz diffusion cell. All experiments were conducted at 37±0.5ºC, for 24 hrs (n=3 ± SD; p<0.05).


In vitro permeation test (IVPT) profiles of (A) Hyaluronic acid gels, (B) Compritol gels, (C) Lactoferrin gels. The studies were performed using excised porcine skin membrane of uniform thickness, mounted between the donor and receiver chambers of a vertical franz diffusion cell. All experiments were conducted at 37±0.5ºC, for 24 hrs (n=3 ± SD; p<0.05).