Injectable long-acting ivacaftor-loaded poly (lactide-co-glycolide) microparticle formulations for the treatment of cystic fibrosis: In vitro characterization and in vivo pharmacokinetics in mice
David S. Nakhla, Aml I. Mekkawy, Youssef W. Naguib, Aaron D. Silva Trenkle, Dylan Gao, Jeong‐Ah Kim, Suhaila O. Alhaj‐Suliman, Timothy M. Acri, Krishna Kumar Patel, Sarah E. Ernst, David A. Stoltz, Michael J. Welsh, Aliasger K. Salem
Abstract
Optimizing a sustained-release drug delivery system for the treatment of cystic fibrosis is crucial for decreasing the dosing frequency and improving patients’ compliance with the treatment regimen. In the current work, we developed an injectable PLGA microparticle formulation loaded with ivacaftor, a CFTR potentiator that increases the open probability of the CFTR anion channel, using a single emulsion solvent evaporation technique. We aimed to study the effect of different parameters on the characteristics of the prepared formulations to select an optimized microparticle formulation to be used in the in vivo pharmacokinetic study in mice. First, ivacaftor-loaded microparticles were prepared while varying the formulation parameters to study their effect on the formulations’ size, morphology, drug loading, encapsulation efficiency, and in vitro release profiles. All the prepared microparticles showed smooth spherical surfaces with internal diameters of 1.91– 6.93 µm, drug loading (DL) of 3.91 – 10.3%, percent encapsulation efficiencies (%EE) of 26.6 – 100%, and an overall slow cumulative release profile. We selected one formulation that showed the best combined %DL and %EE values (8.25, and 90.7%, respectively), with an average particle size of 6.83 µm, and a slow bi-phasic in vitro release profile (up to 6 weeks) to study its in vivo pharmacokinetics in comparison to solubilized ivacaftor following their subcutaneous (SC) and intravenous (IV) administration to mice, respectively. The injected microparticle formulation showed steady plasma levels of ivacaftor over a period of 28 days, and a 6-fold increase in AUC 0 – t (71.6 µg/mL*h) compared to the intravenously injected soluble ivacaftor (12.3 µg/mL*h). Our results suggest that this novel ivacaftor-loaded microparticle formulation could potentially eliminate the need for the frequent daily administration of ivacaftor by people with cystic fibrosis which could improve their compliance and ensure successful treatment outcomes.