Pulmonary peptide delivery: effect of taste-masking excipients on leuprolide suspension metered-dose inhalers.

The purpose of this study was to evaluate the effect of taste-masking excipients on in vitro and in vivo performance of a leuprolide metered-dose inhaler (MDI) suspension formulation. Taste-masking excipients (aspartame and menthol) were added to a leuprolide suspension MDI formulation. The leuprolide MDI formulation with the taste-masking excipients was characterized in terms of milling time, particle size distribution, dose delivery and uniformity, and drug absorption in dogs. The data were compared with a formula that did not contain taste-masking excipients. It was found that the longer milling time for the leuprolide suspension with the taste-masking excipients was required to obtain a similar particle size distribution compared with the formula without taste-masking excipients using a fluid energy mill. Although measurable differences in mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) were not observed between the two formulations, the percent of particles < or = 5 microns and the actuator retention for the formula with the taste-masking excipients were significantly different from the formula without taste-masking excipients using the Marple-Miller cascade impactor. Taste-masking excipients did not show a significant effect on valve delivery and through-can dose uniformity. However, the mean ex-actuator dose was 150.4 mg for the formula with the taste-masking excipients and 162.2 mg for the reference formula, respectively, indicating a significant difference. In tracheostomized dogs, both formulations showed comparable pharmacokinetic parameters including Cmax, Tmax, AUC0-12 and bioavailability (F%), indicating that the taste-masking excipients do not have an effect on lung absorption of leuprolide acetate. Therefore, inclusion of taste-masking excipients in the leuprolide MDI suspension formulation showed a significant impact on drug micronization, exactuator dose, and particle deposition pattern. Mechanistically, the unfavorable performance of leuprolide MDI in the presence of taste-masking excipients could be due to modification of the properties of the suspension itself and alteration of propellant evaporation following actuation.

Pulmonary delivery of a dopamine D-1 agonist, ABT-431, in dogs and humans.

The purpose of this study was to evaluate the feasibility of intrapulmonary delivery of ABT-431, a selective D1 receptor agonist. Following intratracheal instillation of the drug solution, the lung bioavailability was found to be approximately 75% in dogs. An aerosol suspension formulation was then developed by dispersing the drug in tetrafluoroethane, HFC-134a, with the aid of poloxamer 124 and vitamin E. This ABT-431 MDI aerosol formulation showed about 40% of the particles emitted from the valve and actuator system to be under 5 microm in diameter. Also, the primary package (15 mL aluminum container, DF10/ACT-150 valve, and Micron-4-actuator with the orifice 0.4 mm) was satisfactory for accurate and reproducible dosimetry. Using tracheostomized beagle dogs, the C(max) following tracheal administration of 5 mg aerosolized ABT-431 was found to be 13.3+/-0.9 ng ml(-1) and the AUC(0-24) was estimated at 33.2+/-10.6 h ng ml(-1). The lung bioavailability of the aerosolized drug was 34% compared to intravenous injection in dogs. In humans, results from a single rising dose study demonstrated that rapid absorption of ABT-431 following oral inhalation administration resulted in a dose-dependent increase in the area under the plasma-time curve at dosage levels between 3.3 and 13.2 mg. There is a possibility of up to 25% absorption of the drug from human lung. Thus, pulmonary bioavailability of ABT-431 is significantly greater than that of oral administration. Also, these findings suggest that small and lipophilic compounds, especially with hepatic first pass effect, may be effectively delivered systemically using oral inhalation aerosols.