Preformulation and Evaluation of Tofacitinib as a Therapeutic Treatment for Asthma

Abstract

Preformulation studies on tofacitinib citrate, a small molecule JAK3 specific inhibitor, have not been previously reported in literature. We therefore conducted several preformulation studies on tofacitinib citrate, and its free base, to better understand factors that affect its solubility, stability, and solid-state characteristics. Further, the results of the preformulation studies helped facilitate the development of a nebulized formulation of tofacitinib citrate for inhalational delivery to house dust mite allergen-challenged, BALB/c mice as a potential treatment for eosinophilic asthma. The preformulation results indicated tofacitinib having a basic pKa of 5.2, with its stability dependent on pH, ionic strength, and temperature. Degradation of tofacitinib follows apparent first-order kinetics. In order to maximize stability of the drug, ionic strength and temperature should be minimized, with an optimal range pH between 2.0 and 5.0. Additionally, our findings demonstrate that tofacitinib citrate can successfully be nebulized at a suitable droplet size for inhalation (1.2 ± 0.2 μm MMAD) through a nose-only chamber. Animals dosed with tofacitinib citrate demonstrated marked reductions in BAL eosinophils and total protein concentrations following HDM challenge. These data suggest that tofacitinib citrate represents the potential to be an effective therapy for eosinophilic asthma.

Excipient-Free Pure Drug Nanoparticles Fabricated by Microfluidic Hydrodynamic Focusing

“…In general, the pristine drugs showed crystalline or semi-crystalline structure, and they underwent substantial amorphization upon nanonization, as clear from the broadening and, in some cases, the disappearance, of the diffraction peaks that are characteristic of the crystalline drug ( Figure 5 ). For example, in the diffractogram of TOF, the raw drug showed a considerably high crystallinity as demonstrated by a series of sharp and intense diffraction peaks ( Figure 5 c) in accordance with literature [ 93 ]. Conversely, nanonized TOF formed a halo pattern typical of a substantially amorphous material, except for two peaks at 2θ = 31.7 and 2θ = 45.5 that were not observed in the XRD pattern of raw TOF ( Figure 5 c).…”

“…Pristine IMA showed melting temperature ( T m ) at 215 °C ( Figure 6 ). Pristine DAS and TOF showed two melting temperatures at 287 and 318 °C and at 148 and 168 °C, respectively, suggesting the presence of a mixture of different polymorphs [ 93 , 94 , 97 ]. The transitions in pristine TOF were very weak with very broad peaks ( Figure 6 ).…”

Design of experiment-driven stability-indicating RP-HPLC method for the determination of tofacitinib in nanoparticles and skin matrix

“…This indicates that nearly 75% of tofacitinib was degraded. The observed base degradation result was confirmed with the reported study by Younis et al They reported that above the pH ~ 9, tofacitinib citrate showed the highest degree of degradation [37]. In contrast, under oxidative stress conditions, the chromatogram (Fig.…”

Anti-Contractile and Anti-Inflammatory Effects of Diacerein on Isolated Mouse Airways Smooth Muscle and Mouse Asthma Model

“…To solve the problem, a series of anti-inflammatory mediators with different pathogenic targets have been proposed to asthma treatment (Celotti and Laufer, 2001;Zhu et al, 2018). Besides well-known omalizumab (Strunk and Bloomberg, 2006), mepolizumab (Ortega et al, 2014) and benralizumab (Nair et al, 2017), tofacitinib, a Janus kinase-signal transducers and activators of transcription (JAK-STAT) signal inhibitor, has exhibited anti-inflammatory effects in murine asthma models and represent the potential to be an effective treatment for asthma (Younis et al, 2019). Accumulating evidence indicated that anti-inflammatory drugs could exert strong efficacy in asthma patients, which enlighten us that developing new uses of already-approved agents with anti-inflammatory properties might be a simple and effective way to pursue innovation of asthma drugs.…”