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.

Novel Delivery Systems for Improving the Clinical Use of Peptides

“…Improved pulmonary bioavailability was seen in salmon calcitonin microparticles formed by spray drying HP-b-cyclodextrin with either linear or branched PEG chains (Tewes et al, 2011). Microparticles with linear PEG had lower surface energy and better aerodynamic properties, whereas branched PEG salmon calcitonin was more protected from the chemical degradation.…”

Current Development in the Evaluation Methods of Pulmonary Drug Delivery System

“…Control of delivery of drug dose, the absence of drug loss in the instrument, the avoidance of nasal passages and the possible targeting of different regions within the respiratory organ are some of the merits of this exposure system. The powder insufflators are used to deliver various drugs to the lungs in different respiratory and non-respiratory diseases like COPD [86] , asthma [50] , pulmonary embolism [87] , lung cancer [88][89][90] , tuberculosis [72,[91][92][93][94][95][96][97][98] , diabetes [99][100][101] , osteoporosis [102] and cancer [103][104] . The delivery of some immunosuppressant [105] and immunostimulant agents [106] were also reported.…”

Formulation, stability and pharmacokinetics of sugar-based salmon calcitonin-loaded nanoporous/nanoparticulate microparticles (NPMPs) for inhalation

“…In vivo studies were performed as described by Tewes et al (2011). The compliance of this study with EC Directive 86/609 was reviewed and approved by the Trinity College Dublin ethical committee.…”