Templated Open Flocs of Anisotropic Particles for Pulmonary Delivery with Pressurized Metered Dose Inhalers

• Published in: Journal of pharmaceutical sciences Vol. 99; no. 7; pp. 3150 - 3165
• Main Authors: Tam, Jasmine M., Engstrom, Josh D., Ferrer, Domingo, Williams, Robert O., Johnston, Keith P.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.07.2010; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Administration, Inhalation; Aerosols - chemistry; Antifungal Agents - administration & dosage; Biological and medical sciences; General pharmacology; Hydrocarbons, Fluorinated - chemistry; Itraconazole - administration & dosage; Medical sciences; Metered Dose Inhalers; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; protein delivery; pulmonary delivery/absorption; pulmonary drug delivery; stabilization; suspensions; suspensions; stabilization; pulmonary delivery/absorption; protein delivery; pulmonary drug delivery; Delivery system; Pharmaceutical technology; Stabilization; Suspension; Drug carrier; Intrapulmonary administration; Protein; Particle; Absorption; Anisotropy; Dosage form; Metered dose inhaler; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.22091

The challenges in forming stable drug suspensions in hydrofluoroalkane (HFA) propellants have limited drug dosages and efficiency of drug delivery with pressurized metered dose inhalers (pMDI). Herein, stable suspensions of weakly flocculated particles, in the shape of thin plates or needles, of a poorly water-soluble drug, itraconazole (Itz), are efficiently delivered by pMDI at high doses, up to 2.4 mg/actuation. These anisotropic particles pack inefficiently and form low-density flocs that stack upon each other to prevent settling. In contrast, spherical particles formed dense aggregates that settled within minutes. Upon actuation of the pMDI, atomized propellant droplets shear apart and thus template the highly friable flocs. Evaporation of the HFA compacts the flocs to yield porous particles with optimal aerodynamic properties. High fine particle fractions (49–64%) were achieved with the stable suspensions for drug loadings up to 50mg/mL. Furthermore, the micron-sized particles, ideal for pulmonary delivery, are composed of nanoparticles that dissociate and facilitate rapid dissolution of poorly water-soluble drugs. Pulmonary delivery of stable suspensions of templated, open flocs is broadly applicable to a range of anisotropic particle morphologies for poorly water-soluble drugs and proteins for efficient delivery of high doses, up to several milligrams, using minimal amounts of excipients.