Mucosal Penetrative Polymeric Micelle Formulations for Insulin Delivery to the Respiratory Tract

Ji-Hyun Kang,1,2,&ast; Jin-Hyuk Jeong,1,&ast; Yong-Bin Kwon,1 Young-Jin Kim,1 Dae Hwan Shin,1 Yun-Sang Park,3 Soonsil Hyun,1 Dong-Wook Kim,4 Chun-Woong Park1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2School of Pharmacy, Institute of New Drug Development, and Respiratory Drug Development Research Institute, Jeonbuk National University, Jeonju, Republic of Korea; 3Research & Development Center, P2K Bio, Cheongju, Republic of Korea; 4College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea&ast;These authors contributed equally to this workCorrespondence: Chun-Woong Park, College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea, Tel +82-43-261-3330, Fax +82-43-268-2732, Email [email protected] Dong-Wook Kim, College of Pharmacy, Wonkwang University, Iksan, 54538, Republic of Korea, Tel +82-63-229-7130, Fax +82-63-850-7309, Email [email protected]: Effective mucosal delivery of drugs continues to pose a significant challenge owing to the formidable barrier presented by the respiratory tract mucus, which efficiently traps and clears foreign particulates. The surface characteristics of micelles dictate their ability to penetrate the respiratory tract mucus. In this study, polymeric micelles loaded with insulin (INS) were modified using mucus-penetrative polymers.Methods: We prepared and compared polyethylene glycol (PEG)-coated micelles with micelles where cell-penetrating peptide (CPP) is conjugated to PEG. Systematic investigations of the physicochemical and aerosolization properties, performance, in vitro release, mucus and cell penetration, lung function, and pharmacokinetics/pharmacodynamics (PK/PD) of polymeric micelles were performed to evaluate their interaction with the respiratory tract.Results: The nano-micelles, with a particle size of < 100 nm, exhibited a sustained-release profile. Interestingly, PEG-coated micelles exhibited higher diffusion and deeper penetration across the mucus layer. In addition, CPP-modified micelles showed enhanced in vitro cell penetration. Finally, in the PK/PD studies, the micellar solution demonstrated higher maximum concentration (Cmax) and AUC0-8h values than subcutaneously administered INS solution, along with a sustained blood glucose-lowering effect that lasted for more than 8 h.Conclusion: This study proposes the use of mucus-penetrating micelle formulations as prospective inhalation nano-carriers capable of efficiently transporting peptides to the respiratory tract.Keywords: insulin, polyethylene glycol, cell-penetrating peptide, aerodynamic properties, mucus penetration