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.

Inhaled Antibiotics for Gram-Negative Respiratory Infections

“…The Tobi Podhaler combines three key elements of an efficient DPI: a powder specifically engineered for use in a DPI, a hard-capsule package containing the drug, and a drug-specific inhalation device (56). In this system, the tobramycin inhalation powder is packed into hard-capsule shells that are individually packaged into blister packs.…”

Influence of physical properties of carrier on the performance of dry powder inhalers

“…The higher the FPF the better the aerosolization efficiency. FPF is influenced by the inhalation device 34 , formulation 35 , 36 (characteristics and downstream processability of the carrier, drug to carrier ratio), and in vitro characteristics of the aerosol 37 (delivery time and rate of delivery).…”

Sharpening nature's tools for efficient tuberculosis control: A review of the potential role and development of host-directed therapies and strategies for targeted respiratory delivery

“…The device, and complementary formulation (Tobi™ Podhaler™), is indicated for cystic fibrosis (CF) patients where lengthy courses of high dose antibiotics as prescribed recurrently. In the past, CF patients were restricted to the use of nebulizers but the T-326 allows high doses of antibiotics to be administered efficiently through the use of re-fillable capsules containing the dry powder formulation, a key property of any potential inhaled TB treatment where large doses are likely to be required [213,214]. DPI's have great potential for inhaled TB treatment due to improved stability of the actives in the dry powder form and cost as the product including formulation can be sold as one.…”

“…PulmoSphere™ particles are porous and in the context of CF contain the antibiotic tobramycin. The sponge-like, drug loaded particles are prepared by an emulsion based spray-drying method resulting in physico-chemical characteristics required for efficient pulmonary targeting such as spherical shape, low micron size and reduced agglomeration [213,214]. Solvent evaporation, using single or double emulsions, is another commonly used method in the production of particles for anti-tubercular treatment [16,25] whereby an emulsion (o/w or w/o/w) containing the active ingredients, polymer and surfactants such as poly vinyl alcohol is homogenised before allowing any organic solvents to evaporate.…”