Systemic Delivery of Biotherapeutics Through the Lung: Opportunities and Challenges for Improved Lung Absorption

Abstract

The development of Exubera(®) (inhaled insulin) has paved the way for consideration of future inhaled biotherapeutic products for systemic delivery. This route of drug delivery favors highly potent small peptides without self-association and large proteins resistant to enzymatic degradation for high bioavailability, while likely resulting in transient therapeutic effects. Improved therapeutic benefits with a needle-free delivery, such as inhaled insulin, are also rational pursuits. Molecules and their formulations must be carefully chosen and designed to optimize the rates of lung absorption and nonabsorptive loss. Novel molecular or formulation approaches, for example, Technosphere(®), Fc-/scFv-fusion protein, PEGylation, polymeric or lipid-based micro/nanoparticles and liposomes, offer opportunities to improve lung absorption and therapeutic duration of some biotherapeutics. Critical assessments are now essential as to their therapeutic benefits, safety, patient acceptance and market competition, as carried out for Exubera.

Optimal PEGylation can Improve the Exposure of Interferon in the Lungs Following Pulmonary Administration

“…PEGylation also has the potential to improve the chemical stability of proteins during aerosol formation, to decrease antigenicity/immunogenicity in the lungs by masking antigen binding sites and to mask protein charges, promoting mucoadhesion and increased diffusion through the respiratory mucus . Importantly, PEGylation can also reduce the rate of absorption across the alveolar–capillary membrane and increase local exposure of lung resident diseases to a single protein dose, however, intrinsic biological activity of the protein is generally reduced by the presence of the PEG . There is therefore a fine balance between the in vitro activity of a PEGylated or native protein and therapeutic efficacy, which is a product of both lung exposure and activity.…”

“…22 Importantly, PEGylation can also reduce the rate of absorption across the alveolar-capillary membrane and increase local exposure of lung resident diseases to a single protein dose, however, intrinsic biological activity of the protein is generally reduced by the presence of the PEG. 23 There is therefore a fine balance between the in vitro activity of a PEGylated or native protein and therapeutic efficacy, which is a product of both lung exposure and activity. The net effect of PEGylation is dependent in large part on the nature of the protein as well as the size of the conjugated PEG.…”

Long-term delivery of protein therapeutics

“…For example, cost of effective enzyme inhibitors, adverse effects due to frequent oral administrations in chronic diseases, poor stability of formulations such as liposomes in GI track, poor loading efficiency of protein in particles owing to hydrophililicity, polydispersed size distribution and particle aggregation 17 . Similar limitations are also associated with non-invasive routes of delivery 18, 19 . Moreover, it is challenging to achieve controlled protein delivery for extended duration via ‘patient compliant’ non-invasive routes.…”

Inhalable PEGylated Phospholipid Nanocarriers and PEGylated Therapeutics for Respiratory Delivery as Aerosolized Colloidal Dispersions and Dry Powder Inhalers

“…Selection of PEGylation site is critical for the protein or polypeptide molecule since different amino acids might have a different outcome upon PEGylation [7,8]. PEGylation chemistry and reaction conditions play a vital role in therapeutic properties of peptides [9,10]. …”