The inhaled medicines pipeline is changing, expanding from conventional small molecules towards proteins, peptides, nucleic acids and other complex therapeutics. Pulmonary delivery could broaden the opportunities for complex therapeutics, supporting both local treatment in the lung and systemic delivery.
New therapeutics require new approaches to delivery. Preserving drug integrity through storage, aerosolisation and administration is becoming as important as generating the right aerosol and achieving efficient lung delivery. Delivery technology is therefore becoming an early strategic development choice. Soft mist inhalers are particularly well positioned to address these emerging requirements and potentially enable the next generation of complex inhaled therapies.
Emerging Opportunity for Pulmonary Delivery of Biologics
Pulmonary delivery of biologics is moving beyond recombinant proteins towards a broader range of therapeutic modalities with five biologics currently approved for direct airway delivery. Specifically, inhaled genetic medicines is emerging with multiple programmes exploring mRNA and viral-vector approaches for cystic fibrosis (CF) and primary ciliary dyskinesia (PCD).
While growth in biologic therapies remains dominated by injectable products, pulmonary delivery offers an attractive alternative for selected biologics, enabling both direct treatment of the respiratory tract and systemic delivery. The lung’s large surface area, thin epithelial barrier and extensive vascular network can support rapid absorption while bypassing gastrointestinal degradation and first-pass hepatic metabolism. As the broader biologics pipeline is predominantly formulated as liquids, liquid inhalation appears to be Yet pulmonary administration brings its own challenges. Formulation stability, aerosol generation, device compatibility, dose delivery and regional deposition are closely interconnected, and a biologic stable in its primary container may not retain its integrity during aerosolisation. For advanced biologics, the delivery system should therefore be considered an integral part of therapeutic development rather than a downstream device or packaging decision. New Therapeutics Demand New Delivery Technologies Biologics place specific demands on delivery: proteins are susceptible to aggregation, denaturation and degradation, while mRNALNP formulations require preservation of both the nucleic acid payload and nanoparticle structure.
The choice of formulation and delivery technology is therefore closely linked. Dry-powder approaches may improve stability but introduce mechanical and thermal stresses during processing, while liquid delivery avoids some of these steps but requires careful control of stability, sterility and aerosolisation compatibility. Device selection consequently becomes part of the formulation strategy. The challenge is not simply to generate a respirable aerosol, but to do so while preserving integrity and biological function. For complex biologics, delivery technology is an early development choice with consequences for formulation, CMC and programme progression. Low-Shear Aerosolisation Becomes a Critical Quality Attribute For sensitive mRNA-LNP and other nanoparticle formulations, aerosolisation must generate a respirable aerosol while minimising mechanical and interfacial stresses that can disrupt the carrier and compromise the encapsulated payload.⁵ Soft mist inhalers offer an attractive alternative to conventional nebulisation, with the aerosol-generation mechanism playing an important role in preserving formulation integrity. Collidingjet systems such as Respimat® form droplets through impinging liquid jets, whereas Rayleigh-based systems such as the Resyca PFSI® exploit the natural instability of micronscale liquid jets to generate the aerosol.
These fundamentally different aerosolgeneration mechanisms also differ in the energy and mechanical stress imparted to the formulation. High aerosolisation energy has been associated with increased lipid-carrier disruption, loss of encapsulated material and mRNA degradation, while low aerosolisation energy such as for Rayleigh breakup has shown improved preservation of nanoparticle size, encapsulation, mRNA integrity and biological functionality compared with the other nebuliser and SMI technologies (Figure 1).7–9 Current evidence remains predominantly in vitro and formulation-specific, but as payloads become more complex and sensitive, aerosolisation stress should be considered. Device performance must therefore extend beyond aerosol characteristics: the relevant question is not only whether a device produces the required aerosol, but whether it preserves and delivers the functional therapeutic. Low energy Rayleigh breakup offers a promising approach where biologic and nanoparticle integrity is critical. a natural route, also reflected by in 79% of current inhaled biologic programmes using nebulised delivery.
