Systemic delivery of parathyroid hormone (1-34) using inhalation dry powders in rats.
The aim of this work was to prepare and characterize inhalation dry powders of human parathyroid hormone (PTH), as well as to assess their efficacy for systemic delivery of the peptide and safety in rats. The powders were prepared by spray-drying using PTH, sugars, dipalmitoylphosphatidylcholine, and/or albumin. They presented an average primary particle diameter of 4.5 microm and tap density of 0.06 g/cm(3), a mass median aerodynamic diameter between 3.9 and 5.9 microm, and reached up to 98% emitted dose and up to 61% fine particle fraction in the multi-stage liquid impinger using a Spinhaler inhaler device. Varying the airflow rate from 30 to 100 L/min had limited influence on the aerodynamic behavior of the aerosols. The absolute PTH bioavailability was 21% after intratracheal administration of the powder formed of PTH/albumin/lactose/dipalmitoylphosphatidylcholine and 18% after subcutaneous injection in rats. Equilibrium dialysis revealed a 78% binding of PTH to albumin and the withdrawal of albumin from the powder increased absolute bioavailability after inhalation from 21 to 34%. No acute inflammation appeared in the lung up to 48 h after a single inhalation. The increased bioavailability of the optimized powder aerosol of PTH makes it a promising alternative to subcutaneous injection.
Codrons
Valérie
V
Université catholique de Louvain, School of Pharmacy, Department of Pharmaceutical Technology, Avenue E. Mounier, 73 UCL 73.20-1200 Brussels, Belgium.
Vanderbist
Francis
F
Verbeeck
Roger K
RK
Arras
Mohammed
M
Lison
Dominique
D
Préat
Véronique
V
Vanbever
Rita
R
D015060:1,2-Dipalmitoylphosphatidylcholine / Q000737:chemistry; D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D016503:Drug Delivery Systems; D006801:Humans; D007785:Lactose / Q000737:chemistry; D008297:Male; D013058:Mass Spectrometry; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D010316:Particle Size; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D011208:Powders; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000737:chemistry; D014199:Trehalose / Q000737:chemistry
D000336:Aerosols; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011208:Powders; D012709:Serum Albumin; D015060:1,2-Dipalmitoylphosphatidylcholine; D014199:Trehalose; D007785:Lactose