Novel propellant-driven inhalation formulations: engineering polar drug particles with surface-trapped hydrofluoroalkane-philes.
Challenges in reformulating pressurized metered-dose inhalers (pMDIs) with hydrofluoroalkane (HFA) propellants, and the potential of inhalation formulations for the delivery of drugs to and through the lungs have encouraged the development of novel suspension-based pMDI formulations. In this work we propose a new methodology for engineering polar drug particles with enhanced stability and aerosol characteristics in propellant HFAs. The approach consists in 'trapping' HFA-philic moieties at the surface of particles, which are formed using a modified emulsification-diffusion method. The trapped moieties act as stabilizing agents, thus preventing flocculation of the otherwise unstable colloidal drug particles. This approach has advantages compared to surfactant-stabilized colloids in that no free stabilizers remain in solution (reduced toxicity), and the challenges associated with the synthesis of well-balanced amphiphiles are circumvented. The methodology was tested by trapping polyethylene glycol (PEG) at the surface of particles of a model polar drug-salbutamol sulfate. Colloidal probe microscopy is used to quantitatively demonstrate the trapping of the HFA-phile at the surface, and the ability of PEG in screening particle-particle cohesive interactions. Both physical stability and the corresponding aerosol characteristics are significantly improved compared to those of a commercial formulation. The fine particle fraction of PEG-coated salbutamol sulfate was observed to be 42% higher than that of Ventolin HFA. The formation of stable dispersions of terbutaline hemisulfate using the same approach, suggests this to be a generally applicable methodology to polar drugs.
Wu
Libo
L
Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202, USA.
Al-Haydari
Mariam
M
da Rocha
Sandro R P
SR
D000085:Acetates / Q000737:chemistry; D000280:Administration, Inhalation; D000335:Aerosol Propellants / Q000737:chemistry*; D000420:Albuterol / Q000008:administration & dosage / Q000737:chemistry; D004058:Diffusion; D004355:Drug Stability; D045703:Emulsifying Agents / Q000737:chemistry; D004655:Emulsions; D005079:Excipients / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D054709:Lecithins / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D008855:Microscopy, Electron, Scanning; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D013500:Surface Tension; D013678:Technology, Pharmaceutical / Q000379:methods*; D013726:Terbutaline / Q000008:administration & dosage / Q000737:chemistry; D014961:X-Ray Diffraction; D005466:Fluorocarbons
D000085:Acetates; D000335:Aerosol Propellants; D000420:Albuterol; D045703:Emulsifying Agents; D004655:Emulsions; D005079:Excipients; D006845:Hydrocarbons, Fluorinated; D054709:Lecithins; D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols; D013726:Terbutaline; C007650:ethyl acetate; C094049:apaflurane; D005466:Fluorocarbons