title: Ultra-fast absorption of amorphous pure drug aerosols via deep lung inhalation.
abstract: A deficiency of most current drug products for treatment of acute conditions is slow onset of action. A promising means of accelerating drug action is through rapid systemic drug administration via deep lung inhalation. The speed of pulmonary drug absorption depends on the site of aerosol deposition within the lung and the dissolution rate and drug content of the deposited particles. Alveolar delivery of fast-dissolving, pure drug particles should in theory enable very rapid absorption. We have previously shown that heating of thin drug films generates vapor-phase drug that subsequently cools and condenses into pure drug particles of optimal size for alveolar delivery. Here we present a hand held, disposable, breath-actuated device incorporating this thermal aerosol technology, and its application to the delivery of alprazolam, an anti-panic agent, and prochlorperazine, an anti-emetic with recently discovered anti-migraine properties. Thermal aerosol particles of these drugs exist in an amorphous state, which results in remarkably rapid drug absorption from the lung into the systemic circulation, with peak left ventricular concentrations achieved within 20 s, even quicker than following rapid (5 s) intravenous infusion. Absorption of the thermal aerosol is nearly complete, with >80% absolute bioavailability found in both dogs and human normal volunteers.
authors.affiliation: Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA. joshr@princeton.edu
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rabinowitz
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lloyd
authors.forename: Patrik
authors.initials: P
authors.lastname: Munzar
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Myers
authors.forename: Steve
authors.initials: S
authors.lastname: Cross
authors.forename: Ramesh
authors.initials: R
authors.lastname: Damani
authors.forename: Reynaldo
authors.initials: R
authors.lastname: Quintana
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Spyker
authors.forename: Pravin
authors.initials: P
authors.lastname: Soni
authors.forename: James V
authors.initials: JV
authors.lastname: Cassella
mesh_terms: D000042:Absorption; D000280:Administration, Inhalation; D000328:Adult; D000336:Aerosols; D000525:Alprazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D000818:Animals; D019540:Area Under Curve; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D004311:Double-Blind Method; D005260:Female; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008855:Microscopy, Electron, Scanning; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000737:chemistry; D011346:Prochlorperazine / Q000008:administration & dosage / Q000493:pharmacokinetics; D014961:X-Ray Diffraction
chemical_list: D000336:Aerosols; D018492:Dopamine Antagonists; D018757:GABA Modulators; D004364:Pharmaceutical Preparations; D011346:Prochlorperazine; D000525:Alprazolam