title: Physical Characterization of Tobramycin Inhalation Powder: I. Rational Design of a Stable Engineered-Particle Formulation for Delivery to the Lungs.
abstract: A spray-dried engineered particle formulation, Tobramycin Inhalation Powder (TIP), was designed through rational selection of formulation composition and process parameters. This PulmoSphere powder comprises small, porous particles with a high drug load. As a drug/device combination, TOBI Podhaler enables delivery of high doses of drug per inhalation, a feature critical for dry powder delivery of anti-infectives for treatment of cystic fibrosis. The objective of this work was to characterize TIP on both the particle and molecular levels using multiple orthogonal physical characterization techniques. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), electron spectroscopy for chemical analysis (ESCA), and Raman measurements show that a TIP particle consists of two phases: amorphous, glassy tobramycin sulfate with a glass transition temperature of about 100 °C and a gel-phase phospholipid (DSPC) with a gel-to-liquid-crystal transition temperature of about 80 °C. This was by design and constituted a rational formulation approach to provide Tg and Tm values that are well above the temperatures used for long-term storage of TIP. Raman and ESCA data provide support for a core/shell particle architecture of TIP. Particle surfaces are enriched with a porous, hydrophobic coating that reduces cohesive forces, improving powder fluidization and dispersibility. The excellent aerosol dispersibility of TIP enables highly efficient delivery of fine particles to the respiratory tract. Collectively, particle engineering has enabled development of TOBI Podhaler, an approved inhaled drug product that meaningfully reduces the treatment burden to cystic fibrosis patients worldwide.
authors.affiliation: Novartis Pharmaceuticals, San Carlos, California 94070, United States.
authors.forename: Danforth P
authors.initials: DP
authors.lastname: Miller
authors.affiliation: Novartis Pharmaceuticals, San Carlos, California 94070, United States.
authors.forename: Trixie
authors.initials: T
authors.lastname: Tan
authors.affiliation: Novartis Pharmaceuticals, San Carlos, California 94070, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Tarara
authors.affiliation: Novartis Pharmaceuticals, San Carlos, California 94070, United States.
authors.forename: John
authors.initials: J
authors.lastname: Nakamura
authors.affiliation: Novartis Pharmaceuticals, San Carlos, California 94070, United States.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Malcolmson
authors.affiliation: Novartis Pharmaceuticals, San Carlos, California 94070, United States.
authors.forename: Jeffry G
authors.initials: JG
authors.lastname: Weers
mesh_terms: D000280:Administration, Inhalation; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016503:Drug Delivery Systems; D004355:Drug Stability; D058995:Dry Powder Inhalers; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy*; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D011208:Powders; D014031:Tobramycin / Q000008:administration & dosage* / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D011208:Powders; D014031:Tobramycin
keywords: TOBI Podhaler; amorphous; pulmonary delivery; spray drying