Miller, Danforth, Tan, Trixie, Nakamura, John, Malcolmson, Richard, Tarara, Thomas and Weers, Jeff (2017) Physical characterization of Tobramycin Inhalation Powder: II. State Diagram of an Amorphous Engineered Particle. Molecular Pharmaceutics. ISSN 10.1021/acs.molpharmaceut.7b00036

Abstract

Tobramycin Inhalation Powder (TIP) is a spray-dried engineered particle formulation used in TOBI® Podhaler™, a drug/device combination for treatment of cystic fibrosis. A TIP particle consists of two phases: amorphous, glassy tobramycin sulfate and a gel-phase phospholipid (DSPC). The objective of this work was to characterize both the amorphous and gel phases following exposure of TIP to a broad range of relative humidity and temperature. Because changes in either particle morphology or the solid-state form of the drug could affect drug delivery or biopharmaceutical properties, understanding physical stability was critical to development and registration of this product. This characterization included morphological assessments of particles, thermal analysis to measure the gel-to-liquid crystalline phase transition (Tm) and the glass transition temperature (Tg), enthalpy relaxation measurements to determine structural relaxation times, and gravimetric vapor sorption to measure moisture sorption isotherms of TIP and its components. Collectively, these data enabled development of a state diagram for TIP, a map of the environmental conditions under which physical stability can be expected. This diagram shows that, under long-term storage conditions, TIP is at least 50°C below the Tg of the amorphous phase and at least 40°C below the Tm of the gel phase. Enthalpy relaxation measurements demonstrate that the characteristic structural relaxation times under these storage conditions are many orders of magnitude greater than that at Tg. These data, along with long-term physicochemical stability studies conducted during product development, demonstrate that TIP is physically stable, remaining as a mechanical solid over timescales and conditions relevant to a pharmaceutical product. This met a key design goal in the development of TIP: a room-temperature-stable formulation (three years at room temperature) that obviates the need for refrigeration for long-term storage. This has enabled development of TOBI® Podhaler™ - an approved inhaled drug product that meaningfully reduces the treatment burden of cystic fibrosis patients worldwide.

Item Type:	Article
Keywords:	spray drying, pulmonary delivery, amorphous, structural relaxation, glass, state diagram, TOBI® Podhaler™
Date Deposited:	03 May 2017 00:45
Last Modified:	03 May 2017 00:45
URI:	https://oak.novartis.com/id/eprint/31809