Gastric delivery is unachievable for most biopharmaceuticals, so drug developers formulate biologics primarily for intravenous infusion or injection. However, inhaled and nasal delivery options are attracting considerable attention because they enable targeted delivery of a wide range of therapeutic proteins. On 23 June 2020, Mark Parry (technical director at Intertek) presented an “Ask the Expert” webinar that described critical considerations for inhaled and nasal delivery for biologics.

Parry’s Presentation
Because biopharmaceuticals are complex products, developers need compelling reasons to choose inhaled and nasal formulations. Targeted drug delivery is one such reason. As researchers have observed with therapeutics for asthma/chronic obstructive pulmonary disease (COPD) and antibiotics, local administration facilitates delivery of therapeutic doses. That enables developers to reduce the amount of active pharmaceutical ingredient (API) in each unit, often improving a drug’s side-effect profile.

Research on nasal administration is driving discussions about formulation. Until recently, nasal products had been merely topical, but new studies and products show that the nasal route can enable systemic delivery. Developers are leveraging nasal turbinates as a delivery pathway. Those structures provide a large mucosal surface area that facilitates drug absorption. Naloxone (for opioid overdose) and sumatriptan (for migraines) already have been formulated for that pathway, as have some emerging influenza vaccines.

Researchers also are investigating delivery to nasal-associated lymphatic tissue (NALT) and the olfactory region. NALT provides a large mucosal platform, which can help provoke systemic immune responses. The olfactory region offers a “back door” to the brain, enabling delivery of drugs that otherwise cannot pass the blood–brain barrier. That holds promise for treating anxiety, depression, migraines, Alzheimer’s disease, and Parkinson’s disease.

Biologics developers can select from several nasal devices. Solution- and suspension-based sprays are inexpensive and can facilitate biologics administration. But some devices do not tolerate freeze–thaw cycles. Reconstitution of drug product (DP) close to administration and careful device screening and design can circumvent that problem. Many biologics developers favor dry powder, which can increase drug-product stability and longevity.

Pressurized metered-dose inhalers (pMDIs) present significant formulation challenges for biologics, so the focus is on aqueous and solid formulations for pulmonary delivery of biologics. When deciding between aqueous and solid formulations, sponsors must consider the difficulty of particle engineering needed for solid and suspension-based products. A nebulizer solution does not require significant particle engineering, so it is a common target for development. A solution-based DP might not be stable, but vials can tolerate freeze–thaw and lyophilization/reconstitution. When solid dosage forms are targeted, spray drying is best for producing particles of <5 μm.

Inhaled and nasal formulations can provide good flexibility in dosing. Nebulizers can deliver >50 mg per unit, although protein products generate viscosity issues at high doses. Dry powders can provide up to ~10 mg; pMDIs are limited to ~1 mg.

Analytical assays are critical to translating biologics from injectable to inhaled or nasal products. Developers know how their products behave out of a vial, but formulations for the nose and lungs also require characterization of DP emission from devices. Successful translation requires aerodynamic particle-size distribution and emitted-dose/dose-uniformity assessments to establish product specifications.

Questions and Answers
Which is the better option for systemic delivery: inhaled or nasal formulation? Emerging research tends to focus on nasal products for systemic delivery. Inhaled products often perform well in terms of dosing immediacy, but they can raise formulation challenges.

Can inhaled and nasal formulations deliver small proteins such as antibody fragments and nanobodies? Inhaled and nasal delivery can accommodate a wide range of proteins from antibody fragments to large monoclonal antibodies (MAbs). Large MAbs might pose challenges depending on where and how effectively they are delivered. But antibody fragments are within remit, and researchers are investigating inhaled and nasal delivery of messenger RNA (mRNA) and DNA fragments.

How has COVID-19 influenced pharmaceutical industry perceptions about inhaled and nasal products? Researchers have studied mucosal vaccines and pulmonary antivirals and antibiotics extensively, but COVID-19 has jumpstarted industry-wide exploration of inhaled and nasal formulations. Inhaled delivery is likely to gain traction as part of the COVID-19 response and as a larger movement to maximize drug efficacy and optimize dosing requirements for existing therapies.

Watch the full webcast to learn more about nasal delivery technologies now.