Article pubs.acs.org/molecularpharmaceutics
Physical Characterization of Tobramycin Inhalation Powder: I. Rational Design of a Stable Engineered-Particle Formulation for Delivery to the Lungs Danforth P. Miller,* Trixie Tan, Thomas E. Tarara, John Nakamura, Richard J. Malcolmson, and Jeffry G. Weers Novartis Pharmaceuticals, San Carlos, California 94070, United States 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 antiinfectives 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. KEYWORDS: spray drying, pulmonary delivery, amorphous, TOBI Podhaler
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INTRODUCTION Cystic fibrosis (CF) is the most common life-shortening genetic disease in the United States and Northern Europe. The genetic defect results in thickened mucus and causes chronic lung infections in CF patients. Therapies that suppress bacterial loads in the lungs have been shown to reduce the rate of lung function decline in infected patients. Tobramycin Inhalation Solution (TOBI) is commonly used to treat CF patients with chronic pulmonary Pseudomonas aeruginosa infections. This tobramycin product is administered with a standard jet nebulizer. A patient inhales each dose of TOBI in two daily sessions, each of which takes about 20 min. In contrast to this nebulized product, TOBI Podhaler is a new drug-device combination product used to deliver a dry powder aerosol of tobramycin to the lungs. At each dose, a patient inhales a fine powder using a portable dry powder inhaler. While both products have a comparable safety and efficacy profile, TOBI Podhaler offers a far more convenient option for treatment of pseudomonas lung infection in CF patients.1 By delivering a dose in four capsules, TOBI Podhaler reduces the average administration time from 20 min (for TOBI) to about 6 min (in clinical trials, administration time ranged from 2 to 7 min).1 This is a significant saving in time and provides CF patients with more freedom from dosing medication as they are © 2015 American Chemical Society
typically on multiple chronic therapies. Furthermore, the use of a disposable device relieves the patient and caregivers from additional time spent cleaning and disinfecting nebulizer equipment, and the portability of the TOBI Podhaler device enables dose administration without the need for a power supply. Collectively, these benefits markedly relieve a patient’s burden of treatment. Given that preservation of lung function in persons with CF relies upon adherence to therapy, improvements in existing therapies that increase patient adherence improve therapeutic outcomes.2−6 TOBI Podhaler is approved in nearly 70 countries worldwide. As a drug product, TOBI Podhaler integrates three key elements: an engineered powder, the primary package (a hard capsule), and an inhalation device. TOBI Podhaler Capsules consist of Tobramycin Inhalation Powder (TIP) filled into preprinted, size #2 inhalation-grade hard-capsule shells composed of hypromellose (hydroxypropylmethylcellulose, HPMC) and trace amounts of potassium chloride, carrageenan, Special Issue: Advances in Respiratory and Nasal Drug Delivery Received: Revised: Accepted: Published: 2582
February 18, 2015 May 30, 2015 June 8, 2015 June 8, 2015 DOI: 10.1021/acs.molpharmaceut.5b00147 Mol. Pharmaceutics 2015, 12, 2582−2593
Article
Molecular Pharmaceutics
respiratory delivery of fine particles, even those with a geometric size on the order of 2−3 μm. As a result of the decreased attractive forces, these engineered particles do not need to be blended with coarse lactose carrier particles to improve powder fluidization and dispersibility. A high drug load (∼85% tobramycin sulfate) can be achieved, thereby enabling delivery of higher doses of drug per inhalation, a feature critical for dry powder delivery of anti-infectives and other high-dose drugs to the lungs. Robust aerosol performance has been demonstrated in a number of studies conducted during development of TOBI Podhaler. Haynes et al.13 studied aerosol delivery across a range of flow rates (40−85 L per minute) and environmental conditions (10−40 °C at 40% RH; 10−65% RH at 25 °C), providing a broad-based measure of the fluidization and dispersibility of TIP. Delivered dose was greater than 93% of label claim and fine particle dose (FPD
