title: Evaluation of HPβCD-PEG microparticles for salmon calcitonin administration via pulmonary delivery.
abstract: For therapeutic peptides, the lung represents an attractive, noninvasive route into the bloodstream. To achieve optimal bioavailability and control their fast rate of absorption, peptides can be protected by coprocessing with polymers such as polyethylene glycol (PEG). Here, we formulated and characterized salmon calcitonin (sCT)-loaded microparticles using linear or branched PEG (L-PEG or B-PEG) and hydroxypropyl-beta-cyclodextrin (HPβCD) for pulmonary administration. Mixtures of sCT, L-PEG or B-PEG and HPβCD were co-spray dried. Based on the particle properties, the best PEG:HPβCD ratio was 1:1 w:w for both PEGs. In the sCT-loaded particles, the L-PEG was more crystalline than B-PEG. Thus, L-PEG-based particles had lower surface free energy and better aerodynamic behavior than B-PEG-based particles. However, B-PEG-based particles provided better protection against chemical degradation of sCT. A decrease in sCT permeability, measured across Calu-3 bronchial epithelial monolayers, occurred when the PEG and HPβCD concentrations were both 1.6 wt %. This was attributed to an increase in buffer viscosity, caused by the two excipients. sCT pharmacokinetic profiles in Wistar rats were evaluated using a 2-compartment model after iv injection or lung insufflation. The maximal sCT plasma concentration was reached within 3 min following nebulization of sCT solution. L-PEG and B-PEG-based microparticles were able to increase T(max) to 20 ± 1 min and 18 ± 8 min, respectively. Furthermore, sCT absolute bioavailability after L-PEG-based microparticle aerosolization at 100 μg/kg was 2.3 times greater than for the nebulized sCT solution.
authors: School of Pharmacy and Pharmaceutical Sciences, University of Dublin, Trinity College Dublin, Dublin 2, Ireland.
authors: Frederic
authors: F
authors: Tewes
authors: Oliviero L
authors: OL
authors: Gobbo
authors: Maria I
authors: MI
authors: Amaro
authors: Lidia
authors: L
authors: Tajber
authors: Owen I
authors: OI
authors: Corrigan
authors: Carsten
authors: C
authors: Ehrhardt
authors: Anne Marie
authors: AM
authors: Healy
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D001682:Biological Availability; D001692:Biological Transport; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D001980:Bronchi / Q000378:metabolism*; D002116:Calcitonin / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D002460:Cell Line; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D004355:Drug Stability; D029941:Fish Proteins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D006207:Half-Life; D008297:Male; D008422:Materials Testing; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D020545:Respiratory Mucosa / Q000378:metabolism*; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D050071:Bone Density Conservation Agents; D029941:Fish Proteins; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011092:Polyethylene Glycols; C028815:salmon calcitonin; D002116:Calcitonin