Excipients in orally inhaled protein formulations: current examples, challenges, and future directions

Abstract

Inhaled protein therapeutics offer a direct route to the lung and hold strong promise for improving respiratory disease treatment. Their development, however, is complicated by the intrinsic fragility of proteins and the physical stresses imposed during aerosolization. Formulation options are further constrained by the limited number of excipients approved for inhalation, which are crucial for minimizing aggregation, degradation, and loss of delivery efficiency. This review outlines key requirements for inhaled formulations, surveys FDA-approved inhaled biologics and excipients, and highlights emerging formulation strategies and advanced delivery systems. It also discusses future priorities, emphasizing novel excipients, improved stability, and clearer regulatory guidance.

Introduction

Since the US Food and Drug Administration (FDA) approved the first protein therapeutic, Humulin (human recombinant insulin), in 1982, protein therapeutics have revolutionized treatment strategies and become a cornerstone of modern healthcare.(p1) These engineered macromolecules – including cytokines, enzymes, hormones, and antibodies – serve as active pharmaceutical ingredients (APIs) in biotherapeutics.(p2) The clinical and economic impact of protein therapeutics continues to expand. In 2024 alone, 53 new drugs were approved by the European Medicines Agency (EMA), FDA, and Medicines and Healthcare Products Regulatory Agency (MHRA), of which 15 (28%) were protein therapeutics, including recombinant proteins, bispecific antibodies, and monoclonal antibodies (mAbs).(p3) Antibodies remain the dominant class in biotherapeutics, consistently driving innovation and clinical success.

The market growth of protein therapeutics is driven by several factors: (i) unique pharmacological properties compared with small drug molecules, associated with a high specificity/selectivity, fewer off-target effects and better bioavailability(p4),(p5); (ii) clinical demand to face the rising incidence of chronic diseases, primarily autoimmune disorders, cancer, and metabolic conditions(p6); (iii) demand for specific and targeted therapies that adhere to the one-target-one-drug principle in rational drug development(p7); (iv) progress in protein engineering and recombinant technologies(p1); and (v) advances in drug delivery systems that enable personalized medicine approaches.(p8)

Even though protein therapeutics have become the gold standard in the treatment of various chronic ailments, including the management of some lung disorders, nearly all of them are intended for conventional administration, which mainly occurs via the systemic route (intravenous), followed by intramuscular and subcutaneous methods.(p9) These modalities present limitations for pulmonary indications, as they achieve low drug deposition in lung tissue while exposing patients to systemic toxicity.(p10) Indeed, studies report that after intravenous administration, serum concentrations of mAbs can exceed bronchoalveolar levels by 500–10 000-fold, underscoring their poor permeability across endothelial and epithelial barriers.(p11),(p12),(p13) Moreover, intravenous injection exposes non-target tissues to potential adverse effects, including systemic toxicity and cytokine release syndrome. This mismatch highlights the challenge of achieving therapeutic airway concentrations through systemic delivery and strengthens the need for alternative administration routes of administration for protein therapeutics,(p14) such as pulmonary delivery (Figure 1).

Oral inhalation offers a promising solution for targeted therapeutic protein delivery to the lungs via aerosolization. Already established for small-molecule therapies, inhaled delivery of proteins enables high local concentrations within the lung, faster onset of action, and lower systemic exposure. Even at lower doses, inhaled protein therapeutics can provide equal or superior efficacy for treating pulmonary diseases when compared with systemic administration.(p15),(p16) Additional advantages include non-invasiveness and the potential for self-administration, which can improve patient compliance. However, developing protein therapeutics for inhalation delivery presents unique formulation challenges owing to the physical and chemical instability of proteins during aerosolization, which can promote aggregation and compromise therapeutic activity and safety. Excipients play a crucial part in stabilizing inhaled protein therapeutics, maintaining drug product integrity, and mitigating immunogenic responses.(p17) This review highlights current knowledge and gaps in excipient selection for inhaled protein therapeutics, emphasizing the rationale for excipient choice and concentration, their functions in formulation stability, and lessons from approved, patented, and developmental protein therapeutics.

Continue reading here

Bhupinder Kaur, Thomas Sécher, Nathalie Heuzé-Vourc’h, Excipients in orally inhaled protein formulations: current examples, challenges, and future directions, Drug Discovery Today, Volume 31, Issue 3, 2026, 104642, ISSN 1359-6446, https://doi.org/10.1016/j.drudis.2026.104642.

Read more interesting articles on Dry Powder Inhalers (DPI) here:

• Evaluation of powder discharge-based KinetiSolTM (pKSD) as a fast and solvent-free particle engineering process for pulmonary drug delivery
• 100 Years of Pharmaceutical Lactose continuous improvement
• High-dose subcutaneous Administration of Biologics: Overcoming barriers through formulation and device innovation