title: Design of experiments to optimize an in vitro cast to predict human nasal drug deposition.
abstract: BACKGROUND
  Previous studies showed nasal spray in vitro tests cannot predict in vivo deposition, pharmacokinetics, or pharmacodynamics. This challenge makes it difficult to assess deposition achieved with new technologies delivering to the therapeutically beneficial posterior nasal cavity. In this study, we determined best parameters for using a regionally divided nasal cast to predict deposition. Our study used a model suspension and a design of experiments to produce repeatable deposition results that mimic nasal deposition patterns of nasal suspensions from the literature.
  
  
  METHODS
  The seven-section (the nozzle locator, nasal vestibule, front turbinate, rear turbinate, olfactory region, nasopharynx, and throat filter) nylon nasal cast was based on computed tomography images of healthy humans. It was coated with a glycerol/Brij-35 solution to mimic mucus. After assembling and orienting, airflow was applied and nasal spray containing a model suspension was sprayed. After disassembling the cast, drug depositing in each section was assayed by HPLC. The success criteria for optimal settings were based on nine in vivo studies in the literature. The design of experiments included exploratory and half factorial screening experiments to identify variables affecting deposition (angles, airflow, and airflow time), optimization experiments, and then repeatability and reproducibility experiments.
  
  
  RESULTS
  We found tilt angle and airflow time after actuation affected deposition the most. The optimized settings were flow rate of 16 L/min, postactuation flow time of 12 sec, a tilt angle of 23°, nozzle angles of 0°, and actuation speed of 5 cm/sec. Neither cast nor operator caused significant variation of results.
  
  
  CONCLUSIONS
  We determined cast parameters to produce results resembling suspension nasal sprays in the literature. The results were repeatable and unaffected by operator or cast. These nasal spray parameters could be used to assess deposition from new devices or formulations. For human deposition studies using radiolabeled formulations, this cast could show that radiolabel deposition represents drug deposition. Our methods could also be used to optimize settings for other casts.
authors: 1 Respiratory Product Development, Merck Research Labs , Summit, NJ 07901.
authors: Samir A
authors: SA
authors: Shah
authors: Colin J
authors: CJ
authors: Dickens
authors: David J
authors: DJ
authors: Ward
authors: Anna A
authors: AA
authors: Banaszek
authors: Chris
authors: C
authors: George
authors: Walter
authors: W
authors: Horodnik
mesh_terms: D000281:Administration, Intranasal; D002851:Chromatography, High Pressure Liquid; D005990:Glycerol / Q000737:chemistry; D006801:Humans; D008953:Models, Anatomic; D009093:Mucus / Q000737:chemistry; D009297:Nasal Mucosa / Q000378:metabolism*; D059085:Nasal Sprays; D009666:Nose / Q000033:anatomy & histology* / Q000000981:diagnostic imaging; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry; D011859:Radiography; D015203:Reproducibility of Results; D012107:Research Design; D013678:Technology, Pharmaceutical / Q000379:methods*
chemical_list: D059085:Nasal Sprays; D004364:Pharmaceutical Preparations; D011092:Polyethylene Glycols; C515901:Brij 35; D005990:Glycerol