Preformulation and Evaluation of Tofacitinib as a Therapeutic Treatment for Asthma

• Published in: AAPS PharmSciTech Vol. 20; no. 5; p. 167
• Main Authors: Younis, Usir S., Vallorz, Ernest, Addison, Kenneth J., Ledford, Julie G., Myrdal, Paul B.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 16.04.2019
• Subjects: Administration, Inhalation; Allergens; Animals; Anti-Asthmatic Agents - administration & dosage; Anti-Asthmatic Agents - therapeutic use; Asthma - drug therapy; Biochemistry; Biomedical and Life Sciences; Biomedicine; Biotechnology; Drug Compounding; Drug Stability; Female; Mice; Mice, Inbred BALB C; Pharmacology/Toxicology; Pharmacy; Piperidines - administration & dosage; Piperidines - therapeutic use; Pyrimidines - administration & dosage; Pyrimidines - therapeutic use; Pyroglyphidae; Pyrroles - administration & dosage; Pyrroles - therapeutic use; Research Article; Theme: Paul Myrdal Memorial Issue - Pharmaceutical Formulation and Aerosol Sciences; inhalational delivery; eosinophilia; asthma; tofacitinib citrate; tofacitinib
• ISSN: 1530-9932; 1530-9932
• DOI: 10.1208/s12249-019-1377-0

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 p K a 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.