Beyond the Tablet and Injection: A Drug-Specific Framework for Selecting Oral, Buccal, Transdermal, Nasal, and Microneedle Delivery Routes for Peptide and Protein Therapeutics

Abstract

Peptide and protein therapeutics have transformed the treatment of diabetes, endocrine disorders, inflammatory diseases, cancer, and several rare conditions because of their high biological specificity and potent pharmacological activity. However, most of these medicines still depend on injections because their large molecular size, hydrophilicity, structural instability, enzymatic susceptibility, and limited membrane permeability make conventional non-invasive administration difficult. Although oral, buccal, transdermal, nasal, and microneedle systems have developed rapidly, no single route is suitable for every peptide or protein. The choice of delivery route should therefore be based on the characteristics of the individual therapeutic rather than on the general assumption that one route is universally superior. This narrative review proposes a drug-specific framework for selecting alternative delivery routes according to molecular size, potency, dose requirement, half-life, stability, target tissue, permeability, required onset, dosing frequency, patient acceptability, formulation complexity, and translational feasibility. Published evidence concerning oral, buccal, transdermal, nasal, and microneedle delivery was critically examined, with particular attention to the physiological barriers and formulation technologies associated with each route. Oral delivery provides the greatest convenience but is highly sensitive to gastrointestinal degradation and variable absorption. Buccal delivery avoids the gastrointestinal tract and may provide systemic absorption, although limited surface area and salivary clearance remain important constraints. Nasal delivery can provide rapid systemic exposure but is influenced by mucociliary clearance and mucosal tolerability. Conventional transdermal delivery is generally unsuitable for large hydrophilic biologics, whereas microneedles can temporarily bypass the stratum corneum and provide a more realistic transdermal option. The proposed framework emphasizes route–drug matching, recognizing that successful development depends on balancing bioavailability, safety, stability, dose feasibility, patient preference, manufacturing requirements, and regulatory considerations. Such an approach may improve selection of delivery platforms and reduce unnecessary development of formulations that are unlikely to translate clinically.