Pilot Safety, Tolerability, and Pharmacokinetic Human Trial of Propofol Lingual
Spray
Bina Tejura MD1, Christine Broestl MS RD1, Gary Shangold MD2, Mohammed Abd-El Shafy PhD2, Harry Dugger PhD2, Jason Stein MD1, Michael Weiser MD PhD1. 1Manhattan Pharmaceuticals, Inc. New York, NY, 2NovaDel Pharma, Flemington, New Jersey

INTRODUCTION: At present no entirely satisfactory method for producing relatively brief periods of light-to-moderate preprocedural sedation exists, even in supervised inpatient or ambulatory settings. Orally administered sedatives, vary in onset duration and effectiveness. Intravenous sedation requires advanced clinical supervision. As an alternative, we are exploring whether propofol, when titrated via lingual spray,
possesses safety advantages typical of orally administered sedatives, while producing the necessary sedative efficacy. This route of drug delivery was chosen because the oral mucosa is highly permeable, has a rich vascular supply, avoids the first-pass effect associated with many compounds and allows for rapid systemic uptake of appropriately formulated hydrophobic drugs.
METHODS: Following Ethics Committee approval, a pilot, proof of concept study of a spray formulation of propofol was conducted. 12 fasting, healthy adults of both sexes were administered propofol, in a singlecenter, double-blind, placebo-controlled, dose escalating, randomized trial, After initial screening, propofol (20 mg IV) was administered by bolus intravenously. At 3 day intervals thereafter, 100 – 300 µL propofol formulation was sprayed into the oral cavity via a unit dose actuator, and blood samples were taken for later
propofol concentration analysis (HPLC-FL method; >LOQ = >2.5 ng/mL). Safety was assessed via vital signs, SaO2, PtcCO2, oral mucosal examination, and subjective tolerability.
RESULTS: 11 subjects completed the study, without any treatment-related serious adverse events, or subjective intolerance to the lingual spray. 1 subject was withdrawn after IV dosing, due to a protocol violation. All subjects achieved blood levels after IV bolus, without any episodes of apnea. After administration of propofol lingual spray, 8 of 11 subjects achieved measurable blood levels that were statistically significant (p < 0.005, t-test) without any episodes of apnea. In most cases, these levels appeared as early as 4 minutes following lingual spray administration.
CONCLUSIONS: This data demonstrates that a propofol lingual spray formulation is capable of achieving significant and rapid bioavailability when delivered as a fine mist to the oral cavity. Subjective and objective data indicates that lingual spray administration of propofol is safe and well tolerated. With these principles established, work is in progress to optimize our formulation, and then to characterize relevant pharmacokinetic parameters for Propofol Lingual Spray, including Tmax, Cmax and AUC.

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