title: The in vitro and in vivo investigation of inhaled migraine therapies using a novel aerosol delivery system consisting of an air pressurized capsule device (APCD) in combination with a pMDI spacer for endotracheal dosing into beagle dogs.
abstract: BACKGROUND
  Aerosol delivery to animals in preclinical settings has historically been very challenging, requiring the use of techniques, such as intratracheal instillation and dry powder insufflation, that are somewhat invasive, inefficient and not representative of clinical inhalation.
  
  
  OBJECTIVE
  The objective of this work is to develop a system to deliver dry powder to dogs in an efficient and effective manner for the study of new anti-migraine compounds in development.
  
  
  METHODS
  The new device uses a metered aliquot of a dry gas to force dry powder drug from a pre-filled HPMC capsule into an AeroChamber® spacer for subsequent inhalation by the animal.
  
  
  RESULTS
  The delivery of two invesigational migraine drugs via the new device was assessed in vitro using abbreviated Andersen cascade impaction and showed the device is capable of generating a reproducible delivered dose of up to ∼68% with more than 50% of the dose in the respirable range. In vivo studies have also been performed showing that this device effectively delivered the migraine drugs to spontaneously breathing dogs using a proprietary validated dog inhalation model.
  
  
  CONCLUSIONS
  Results confirmed that the air pressurized capsule device (APCD) was effective in delivering the APIs to lungs of the animals. The in vivo data verified the advantages of inhaled delivery over oral delivery for this class of drugs and were used to establish the cardiopulmonary and respiratory side effect liability profile for these compounds.
  
  
  CONCLUSIONS
  This work has demonstrated the utility of this device for quick and accurate screening of prospective drug candidates, representing a significant improvement in ease of use and reprodicibility over current delivery methods.
authors.affiliation: a Respiratory Product Development, Merck Research Laboratories , Rahway , NJ , USA and.
authors.forename: Shari
authors.initials: S
authors.lastname: Sellers
authors.affiliation: a Respiratory Product Development, Merck Research Laboratories , Rahway , NJ , USA and.
authors.forename: Walter
authors.initials: W
authors.lastname: Horodnik
authors.affiliation: b In-Vivo Pharmacology, Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Aileen
authors.initials: A
authors.lastname: House
authors.affiliation: a Respiratory Product Development, Merck Research Laboratories , Rahway , NJ , USA and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wylie
authors.affiliation: b In-Vivo Pharmacology, Merck Research Laboratories , Kenilworth , NJ , USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Mauser
authors.affiliation: a Respiratory Product Development, Merck Research Laboratories , Rahway , NJ , USA and.
authors.forename: Natalie
authors.initials: N
authors.lastname: Garber
authors.affiliation: a Respiratory Product Development, Merck Research Laboratories , Rahway , NJ , USA and.
authors.forename: Yu Elaine
authors.initials: YE
authors.lastname: Pu
authors.affiliation: a Respiratory Product Development, Merck Research Laboratories , Rahway , NJ , USA and.
authors.forename: Julianne
authors.initials: J
authors.lastname: Berry
authors.affiliation: a Respiratory Product Development, Merck Research Laboratories , Rahway , NJ , USA and.
authors.forename: Brent
authors.initials: B
authors.lastname: Donovan
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000378:metabolism; D002214:Capsules; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D058995:Dry Powder Inhalers / Q000379:methods*; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy; D009330:Nebulizers and Vaporizers; D014132:Trachea / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000336:Aerosols; D001993:Bronchodilator Agents; D002214:Capsules
keywords: Abbreviated Andersen cascade impactor; AeroChamber HC MV; dry powder delivery; inhalation; preclinical dosing