title: Regional deposition of mometasone furoate nasal spray suspension in humans.
abstract: Nasal deposition studies can demonstrate whether nasal sprays treating allergic rhinitis and polyposis reach the ciliated posterior nasal cavity, where turbinate inflammation and other pathology occurs. However, quantifying nasal deposition is challenging, because in vitro tests do not correlate to human nasal deposition; gamma scintigraphy studies are thus used. For valid data, the radiolabel must distribute, as the drug, into different-sized droplets, remain associated with the drug in the formulation after administration, and not alter its deposition. Some nasal deposition studies have demonstrated this using homogenous solutions. However, most commercial nasal sprays are heterogeneous suspensions. Using mometasone furoate nasal suspension (MFS), we developed a technique to validate radiolabel deposition as a surrogate for nasal cavity drug deposition and characterized regional deposition and nasal clearance in humans. Mometasone furoate (MF) formulation was spiked with diethylene triamine pentacaetic acid. Both unlabeled and radiolabeled formulations (n = 3) were sprayed into a regionally divided nasal cast. Drug deposition was quantified by high pressure liquid chromatography within each region; radiolabel deposition was determined by gamma camera. Healthy subjects (n = 12) were dosed and imaged for six hours. Scintigraphic images were coregistered with magnetic resonance imaging scans to quantify anterior and posterior nasal cavity deposition and mucociliary clearance. The ratio of radiolabel to unlabeled drug was 1.05 in the nasal cast and regionally appeared to match, indicating that in vivo radiolabel deposition could represent drug deposition. In humans, MFS delivered 86% (9.2) of metered dose to the nasal cavity, approximately 60% (9.1) of metered dose to the posterior nasal cavity. After 15 minutes, mucociliary clearance removed 59% of the initial radiolabel in the nasal cavity, consistent with clearance rates from the ciliated posterior surface. MFS deposited significant drug into the posterior nasal cavity. Both nasal cast validation and mucociliary clearance confirm the radiolabel deposition distribution method accurately represented corticosteroid nasal deposition.
authors.affiliation: Respiratory Product Development, Merck Research Labs, Whitehouse Station, New Jersey, USA.
authors.forename: Samir A
authors.initials: SA
authors.lastname: Shah
authors.forename: Robert L
authors.initials: RL
authors.lastname: Berger
authors.forename: John
authors.initials: J
authors.lastname: McDermott
authors.forename: Pranav
authors.initials: P
authors.lastname: Gupta
authors.forename: David
authors.initials: D
authors.lastname: Monteith
authors.forename: Alyson
authors.initials: A
authors.lastname: Connor
authors.forename: Wu
authors.initials: W
authors.lastname: Lin
mesh_terms: D000328:Adult; D018926:Anti-Allergic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D005260:Female; D006801:Humans; D007553:Isotope Labeling; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D000068656:Mometasone Furoate; D009079:Mucociliary Clearance; D059085:Nasal Sprays; D011244:Pregnadienediols / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D055815:Young Adult
chemical_list: D018926:Anti-Allergic Agents; D059085:Nasal Sprays; D011244:Pregnadienediols; D000068656:Mometasone Furoate