title: Characterization and pharmacokinetic analysis of crystalline versus amorphous rapamycin dry powder via pulmonary administration in rats.
abstract: The pharmacokinetics of inhaled rapamycin (RAPA) is compared for amorphous versus crystalline dry powder formulations. The amorphous formulation of RAPA and lactose (RapaLac) was prepared by thin film freezing (TFF) using lactose as the stabilizing agent in the weight ratio 1:1. The crystalline formulation was prepared by wet ball milling RAPA and lactose and posteriorly blending the mixture with coarse lactose (micronized RAPA/micronized lactose/coarse lactose=0.5:0.5:19). While both powders presented good aerosolization performance for lung delivery, TFF formulation exhibited better in vitro aerodynamic properties than the crystalline physical mixture. Single-dose 24h pharmacokinetic studies were conducted in Sprague-Dawley rats following inhalation of the aerosol mist in a nose-only inhalation exposure system. Lung deposition was higher for the crystalline group than for the TFF group. Despite higher pulmonary levels of drug that were found for the crystalline group, the systemic circulation (AUC₀₋₂₄) was higher for the amorphous group (8.6 ngh/mL) than for crystalline group (2.4 ngh/mL) based on a five-compartmental analysis. Lung level profiles suggest that TTF powder stays in the lung for the same period of time as the crystalline powder but it presented higher in vivo systemic bioavailability due to its enhanced solubility, faster dissolution rate and increased FPF at a more distal part of the lungs.
authors.affiliation: The University of Texas at Austin, College of Pharmacy, Division of Pharmaceutics, Austin, TX, USA.
authors.forename: Simone R
authors.initials: SR
authors.lastname: Carvalho
authors.affiliation: The University of Texas at Austin, Drug Dynamics Institute, College of Pharmacy, Austin, TX, USA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Watts
authors.affiliation: The University of Texas Health Science Center at San Antonio, Department of Medicine, Division of Pulmonary Diseases/Critical Care Medicine, San Antonio, TX, USA.
authors.forename: Jay I
authors.initials: JI
authors.lastname: Peters
authors.affiliation: The University of Texas at Austin, College of Pharmacy, Division of Pharmaceutics, Austin, TX, USA; Shandong University, School of Medicine, Department of Pharmacology, Jinan, People's Republic of China.
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.affiliation: The University of Texas at Austin, College of Pharmacy, Division of Pharmaceutics, Austin, TX, USA.
authors.forename: Soraya
authors.initials: S
authors.lastname: Hengsawas
authors.affiliation: Rutgers, The State University of New Jersey, School of Engineering, Department of Chemical and Biochemical Engineering, Piscataway, NJ, USA.
authors.forename: Manuel S
authors.initials: MS
authors.lastname: Escotet-Espinoza
authors.affiliation: The University of Texas at Austin, College of Pharmacy, Division of Pharmaceutics, Austin, TX, USA. Electronic address: bill.williams@austin.utexas.edu.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Williams
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols / Q000737:chemistry; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D019540:Area Under Curve; D001992:Bronchoalveolar Lavage Fluid; D003460:Crystallization; D008168:Lung / Q000187:drug effects*; D008855:Microscopy, Electron, Scanning; D009330:Nebulizers and Vaporizers; D010316:Particle Size; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage*; D012995:Solubility; D013696:Temperature; D013818:Thermogravimetry; D014961:X-Ray Diffraction
chemical_list: D000336:Aerosols; D000900:Anti-Bacterial Agents; D011208:Powders; D020123:Sirolimus
keywords: Dry powder; Formulation delivery; Inhalation; Particle engineering; Pharmacokinetics; Rapamycin; Thin film freezing