title: Variability in Delivered Dose from Pressurized Metered-Dose Inhaler Formulations Due to a Delay Between Shake and Fire.
abstract: BACKGROUND
  Pressurized metered-dose inhalers (pMDIs) should be shaken before use to prevent creaming or sedimentation of the drugs in solution; however, data published on this topic are limited, and it is rarely specified how soon after shaking the device should be actuated. Delays between shaking and firing the pMDI have previously been shown to cause significant inhomogeneity in delivered dose. We studied the effect of various shake-fire delays on the drug delivered from five commercially available pMDIs commonly prescribed for asthma and chronic obstructive pulmonary disease to assess the potential variability in delivered dose.
  
  
  METHODS
  The pMDI formulations tested were the Flovent HFA, Ventolin Evohaler, Airomir Inhaler, and Symbicort (suspension pMDIs), and the QVAR 100 Inhaler (solution pMDI). Each pMDI was shaken for 5 seconds before attachment to a dosage unit sampling apparatus collection tube and filter, and it was actuated once with shake-fire delays of 0, 5, 10, 20, 30, 40, 50, and 60 seconds. Analysis of the eluates from the collection tubes and filters was performed by using high-performance liquid chromatography. Three of each pMDI were tested twice with each time delay.
  
  
  RESULTS
  All of the suspension pMDIs produced variable amounts of drug over the shake-fire delays tested. A comparison of the delivered doses after the 0- and 60-second delays showed that the drug delivered increased for the Flovent HFA (320%), Ventolin Evohaler (346%), and Airomir Inhaler (230%) pMDIs; decreased for the Symbicort budesonide (75%) and formoterol fumarate (76%) pMDI; and remained consistent for the QVAR 100 Inhaler pMDI.
  
  
  CONCLUSIONS
  The amount of drug delivered can vary widely over different shake-fire delays with suspension pMDIs. Therefore, guidance should be given to users/caregivers on the timing of firing after shaking their device, particularly with pediatrics, who may take time to become receptive to accepting their medication after pMDI shaking and before dose administration.
authors.affiliation: 1 Philips Respironics Respiratory Drug Delivery (UK) Ltd, a business of Philips Electronics UK Limited, Chichester, United Kingdom .
authors.forename: Ross H M
authors.initials: RH
authors.lastname: Hatley
authors.affiliation: 1 Philips Respironics Respiratory Drug Delivery (UK) Ltd, a business of Philips Electronics UK Limited, Chichester, United Kingdom .
authors.forename: Jacob
authors.initials: J
authors.lastname: Parker
authors.affiliation: 1 Philips Respironics Respiratory Drug Delivery (UK) Ltd, a business of Philips Electronics UK Limited, Chichester, United Kingdom .
authors.forename: John N
authors.initials: JN
authors.lastname: Pritchard
authors.affiliation: 2 Respironics, Inc., A Philips Healthcare Company , Murrysville, Pennsylvania.
authors.forename: Dirk
authors.initials: D
authors.lastname: von Hollen
mesh_terms: D000280:Administration, Inhalation; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D004867:Equipment Design; D006801:Humans; D036501:Metered Dose Inhalers; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents
keywords: creaming; delivered drug; formulation; pressurized metered-dose inhaler (pMDI); sedimentation; shake-fire delay