Inhalation of a dry powder tobramycin PulmoSphere formulation in healthy volunteers.

STUDY OBJECTIVES: To evaluate the efficiency and reproducibility of pulmonary delivery of an investigational tobramycin PulmoSphere formulation (PStob) [Inhale Therapeutic Systems; San Carlos, CA] by a passive dry powder inhaler, and to compare serum concentrations and whole-lung deposition with a commercial nebulized tobramycin product (TOBI; Chiron Corporation; Seattle, WA). DESIGN: A five-period, open-label, nonrandomized crossover study. PARTICIPANTS: Fourteen healthy volunteers were studied, and 12 completed the study. INTERVENTIONS: PStob powder was manufactured using lipid-based PulmoSphere technology, producing highly dispersible porous particles. PStob was radiolabeled with (99m)Tc, and in vitro experiments confirmed it as a valid drug marker. To identify whole-lung distribution via scintigraphy, subjects inhaled contents of a single capsule (72 L/min) containing 25 mg of (99m)Tc-labeled PStob (13.5 mg of tobramycin free base) in periods 1 to 3. In period 4, subjects received (99m)Tc nebulized tobramycin, approximately 2.5 mL of 300 mg/5 mL. Deposition and blood samples were obtained. In period 5, six 25-mg doses of unlabeled PStob (81 mg of tobramycin base) were inhaled and blood samples were collected. MEASUREMENTS AND RESULTS: Mean whole-lung deposition of PStob was 34 +/- 6% and nebulized tobramycin was 5 +/- 2%. Peak tobramycin concentration in serum (Cmax) values were 0.6 microg/mL with PStob and 0.28 microg/mL after nebulized tobramycin. Serum area under the curve was 4.4 microg x h/mL vs 2.1 micro g x h/mL for nebulized tobramycin. Median time to Cmax for PStob was comparable to nebulized tobramycin. CONCLUSIONS: The aerosol doses of PStob (25 mg and 150 mg) were well dispersed and tolerated. Serum drug concentrations matched scintigraphy data and were roughly twice that of the comparator. Intrasubject dose variability for three equivalent periods did not exceed 18% relative SD. PStob Cmax (0.6 microg/mL) was well below the toxic threshold (2 micro g/mL).

Radionuclide imaging technologies and their use in evaluating asthma drug deposition in the lungs.

Whole lung and regional lung deposition of inhaled asthma drugs in the lungs can be quantified using either two-dimensional or three-dimensional radionuclide imaging methods. The two-dimensional method of gamma scintigraphy has been the most widely used, and is currently considered the industry standard, but the three-dimensional methods (SPECT, single photon emission computed tomography; and PET, positron emission tomography) give superior regional lung deposition data and will undoubtedly be used more frequently in future. Recent developments in radionuclide imaging are described, including an improved algorithm for assessing regional lung deposition in gamma scintigraphy, and a patent-protected radiolabelling method (TechneCoat), applicable to both gamma scintigraphy and SPECT. Radionuclide imaging data on new inhaled asthma products provide a milestone assessment, and the data form a bridge between in vitro testing and a full clinical trials program, allowing the latter to be entered with increased confidence.

Deposition and pharmacokinetics of budesonide from the Miat Monodose inhaler, a simple dry powder device.

Dry powder inhalers (DPIs) are used to deliver asthma drugs to patients, but lung deposition may depend upon the degree of inspiratory effort. The pulmonary deposition of the glucocorticosteroid budesonide (SMB-Galephar) has been assessed in 12 asthmatic patients when delivered by the Monodose inhaler (Miat, Milan, Italy); the Pulmicort Turbuhaler DPI (AstraZeneca, Lund, Sweden) was used as a comparator product. Patients inhaled from each device with maximal or sub-maximal inspiratory effort: Monodose inhaler 90 vs 45 l/min; Turbuhaler DPI 60 vs 30 l/min. The formulations were radiolabelled with (99m)Tc, and deposition of budesonide was quantified by gamma scintigraphy. Mean (SD) whole lung deposition for the Monodose inhaler (% capsule dose), was independent of inspiratory effort (maximal: 21.4 (4.3)%; sub-maximal: 21.4 (7.5)%), while lung deposition for the Turbuhaler DPI (% metered dose) fell significantly with decreasing inspiratory effort (maximal: 25.1 (6.1)%; sub-maximal: 18.5 (6.5)%; P<0.05). The plasma concentrations of budesonide showed the same trends as the whole lung deposition data. The Monodose inhaler showed inspiratory effort-independent drug delivery characteristics, and could prove be a valuable low-cost alternative to more complex devices such as the Turbuhaler DPI. The Monodose inhaler may be especially useful in groups of patients unable to inhale maximally through DPIs, including young children and adult patients with severe respiratory impairment.

Improved lung delivery from a passive dry powder inhaler using an Engineered PulmoSphere powder.

PURPOSE: To assess the pulmonary deposition and pharmacokinetics of an engineered PulmoSphere powder relative to standard micronized drug when delivered from passive dry powder inhalers (DPIs). METHODS: Budesonide PulmoSphere (PSbud) powder was manufactured using an emulsion-based spray-drying process. Eight healthy subjects completed 3 treatments in crossover fashion: 370 microg budesonide PulmoSphere inhaled from Eclipse DPI at target PIF of 25 L x min(-1) (PSbud25), and 50 L x min(-1) (PSbud50), and 800 microg of pelletized budesonide from Pulmicort Turbuhaler at 60 L x min(-1)(THbud60). PSbud powder was radiolabeled with 99mTc and lung deposition determined scintigraphically. Plasma budesonide concentrations were measured for 12 h after inhalation. RESULTS: Pulmonary deposition (mean +/- sd) of PSbud was 57+/-7% and 58+/-8% of the nominal dose at 25 and 50 L x min(-1), respectively. Mean peak plasma budesonide levels were 4.7 (PSbud25), 4.0 (PSbud50), and 2.2 ng x ml(-1) (THbud60). Median t(max) was 5 min after both PSbud inhalations compared to 20 min for Turbuhaler (P < 0.05). Mean AUCs were comparable after all inhalations, 5.1 (PSbud25), 5.9 (PSbud50), and 6.0 (THbud60) ng x h x ml(-1). The engineered PSbud powder delivered at both flow rates from the Eclipse DPI was twice as efficiently deposited as pelletized budesonide delivered at 60 L x min(-1) from the Turbuhaler. Intersubject variability was also dramatically decreased for PSbud relative to THbud. CONCLUSION: Delivery of an engineered PulmoSphere formulation is more efficient and reproducible than delivery of micronized drug from passive DPIs.

In vivo lung deposition of hollow porous particles from a pressurized metered dose inhaler.

PURPOSE: PulmoSphere particles are specifically engineered for delivery by the pulmonary route with a hollow and porous morphology, physical diameters < 5 microm, and low tap densities (circa 0.1 g x cm(-3)). Deposition of PulmoSphere particles in the human respiratory tract delivered by pressurized metered dose inhaler (pMDI) was compared with deposition of a conventional micronized drug pMDI formulation. METHODS: Nine healthy nonsmoking subjects (5 male, 4 female) completed a two-way crossover gamma scintigraphic study, assessing the lung and oropharyngeal depositions of albuterol sulfate, formulated as 99mTc-radiolabeled PulmoSphere particles or micronized particles (Ventolin Evohaler, GlaxoSmithKline, Ltd.) suspended in HFA-134a propellant. RESULTS: Mean (standard deviation) lung deposition, (% ex-valve dose) was doubled for the PulmoSphere formulation compared with Evohaler pMDI (28.5 (11.3) % vs. 14.5 (8.1) %, P < 0.01), whereas oropharyngeal deposition was reduced (42.6 (9.0) % vs. 72.0 (8.0) %, P < 0.01). Both PulmoSphere and Evohaler pMDIs gave uniform deposition patterns within the lungs. CONCLUSIONS: These data provided "proof of concept" in vivo for the PulmoSphere technology as a method of improving targeting of drugs to the lower respiratory tract from pMDIs, and suggested that the PulmoSphere technology may also be suitable for the delivery of systemically acting molecules absorbed via the lung.