title: Development of a dry powder inhaler, the Ultrahaler, containing triamcinolone acetonide using in vitro-in vivo relationships.
abstract: Triamcinolone acetonide (TAA) is safe and effective corticosteroid that is marketed as an MDI (metered dose inhaler) (Azmacort) for the treatment of asthma. A novel dry powder inhaler (DPI), the Ultrahaler, has been developed to deliver Azmacort as another alternative to provide non-CFC formulation for the asthmatic patients. The Ultrahaler is breath actuated and, unlike MDI, does not require coordination of inhalation with the actuation of the device. However, with the Ultrahaler device, like any dry powder inhalation device, the challenge was the on-target and uniform delivery of the drug at the site of action (lungs) with different dose strengths. Due to the complexities of oral inhaled formulations and the topical nature of drug delivery to the lung for efficacy, the reformulation requires careful consideration and support throughout their development, using a combination of in vitro and in vivo studies. This paper describes in vitro studies and two clinical pharmacokinetic studies conducted in a sequence that helped to establish optimum doses for the Ultrahaler. In vitro data were used to guide the initial selection of doses that were then compared in vivo using a pharmacokinetic study with a charcoal block. The in vitro tests included quantifying the target-delivered dose, dose uniformity throughout the life of the device, and the particle size distribution. Particle size distribution was measured using multistage liquid impinger (MSLI) or the Andersen Cascade Impactor (ACI). For in vitro testing, TAA was measured by HPLC methods. Based on the preliminary in vitro data for the respirable fraction, dose strengths with an MDI and the Ultrahaler for the first study were determined. The in vivo assessment consisted of a four-way crossover study following oral inhalation using both MDI (75 and 225 microg/actuation, reference treatment) and comparable respirable doses in the DPI (130 and 360 microg/actuation) devices in healthy volunteers in the presence (lung deposition) and absence (lung and oropharynx deposition) of the charcoal block. Plasma TAA concentrations were determined using a radioimmunoassay (RIA) method. The in vitro data also showed dose proportionality with DPI formulation, and the doses delivered were within 13% of the target doses. A measure of dose uniformity, the relative standard deviation (%RSD) of dose, was less than 15%. Plasma TAA exposure of DPI formulations was compared with that of MDI formulations. Mean ratios (DPI/MDI) of the AUCinf were close to unity for the lower dose strength. However, for the higher dose strength, plasma exposure was higher with the Ultrahaler formulation as compared with the MDI formulation (mean AUCinf DPI/MDI ratios: 1.96). These differences seem to be due to less than proportional increases in the MDI formulation. Based on these results and using the higher dose strength of the MDI as the comparator, the new dose strengths of the Ultrahaler were chosen, ie, 100, 225, and 450 mug/actuation. Plasma TAA concentrations were measured by LC/MS/MS methods. The mean TAA concentrations and AUCinf and Cmax values increased in a dose-proportional manner with an increase in dose for the DPI formulation. The pharmacokinetic parameters showed low variability (10%-33%). Fine particle mass (in vitro testing) and TAA exposure in plasma following DPI administration were compared. Fine particle performance in vitro related well with in vivo pharmacokinetic performance (R=AUCinf-0.9998, Cmax-0.9956). In conclusion, in vitro and in vivo data were in agreement and good control over the target-dose delivery and dose proportionality could be achieved in the early stages of the development of the Ultrahaler device and were critical in guiding and ensuring the success of the reformulation efforts for Azmacort.
authors.affiliation: Aventis, Holmes Chapel, United Kingdom.
authors.forename: Joe G P
authors.initials: JG
authors.lastname: Lim
authors.forename: Bharti
authors.initials: B
authors.lastname: Shah
authors.forename: Shashank
authors.initials: S
authors.lastname: Rohatagi
authors.forename: Alex
authors.initials: A
authors.lastname: Bell
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011208:Powders; D013678:Technology, Pharmaceutical; D014018:Tissue Distribution; D014222:Triamcinolone Acetonide / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D005938:Glucocorticoids; D011208:Powders; D014222:Triamcinolone Acetonide