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.
Zheng
J Y
JY
Pharmaceutical Products Division, Formulation Development Center, Abbott Laboratories, 1401 Sheridan Road, North Chicago, IL 60064-6246, USA. zhengy99@yahoo.com
Fulu
M Y
MY
Lee
D Y
DY
Barber
T E
TE
Adjei
A L
AL
D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D001218:Aspartame / Q000008:administration & dosage / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004285:Dogs; D016503:Drug Delivery Systems / Q000295:instrumentation* / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods; D005079:Excipients / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007442:Intubation, Intratracheal; D016729:Leuprolide / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008168:Lung / Q000378:metabolism; D008610:Menthol / Q000008:administration & dosage / Q000493:pharmacokinetics; D009330:Nebulizers and Vaporizers / Q000706:statistics & numerical data*; D010316:Particle Size; D010455:Peptides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013535:Suspensions / Q000008:administration & dosage / Q000493:pharmacokinetics; D013649:Taste / Q000187:drug effects* / Q000502:physiology
D000336:Aerosols; D005079:Excipients; D010455:Peptides; D013535:Suspensions; D008610:Menthol; D016729:Leuprolide; D001218:Aspartame