Pulmonary Peptide Delivery: Effect of Taste-Masking Excipients on Leuprolide Suspension Metered-Dose Inhalers

Abstract

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.

Taste Masking Technologies in Oral Pharmaceuticals: Recent Developments and Approaches

“…Zheng et al [128] evaluated the effect of tastemasking excipients (aspartame and menthol) on in vitro and in vivo performance of a Leuprolide metered-dose inhaler (MDI) suspension formulation. 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 fluidized energy mill.…”

Optimized dose delivery of the peptide cyclosporine using hydrofluoroalkane‐based metered dose inhalers

“…Pulmonary drug delivery is an important delivery route for the treatment of lung diseases, such as asthma and chronic obstructive pulmonary disease. This administration route is also being investigated as a potentially advantageous delivery route for proteins and peptides, examples of which are insulin,1–3 leuprolide,4,5 and cyclosporine 6. Degradation due to the acidic stomach environment and enzymatic degradation throughout the gastrointestinal tract have traditionally made oral delivery of therapeutic proteins and peptides problematic.…”

Formulating Drugs for Inhalers and Stability Issues

“…Examples of novel pMDI excipients include: novel€ surfactants (e.g. 3 M oligolactic acid, acyl amide acids, monofunctionalised M-PEGS, [50][51][52] taste masking excipients [53] microemulsion excipients, [54,55] microspheres and hollow porous microspheres [29,56] cyclodextrins [57] nanoparticles [58] and alternative propellant systems (DME and propane) [59].…”