Introduction: Menthol, a bioactive terpene alcohol from Mentha piperita L., activates epidermal TRPM8 cold receptors, so epidermal drug concentration is the most relevant pharmacological endpoint for topical analgesic applications. Semi-solid extrusion 3D printing enables precise layer-by-layer PVA matrix construction, potentially creating more homogeneous drug distribution than conventional solvent casting.

Methods: PVA-based films (PVA 10%, glycerol 3%) containing menthol (5% w/w), benzocaine (5% w/w), and capsaicin (0–1% w/w) were manufactured by 3D printing (n=12) and solvent casting (n=12) using matched formulations. Ex vivo permeation studies used human abdominal skin from 10 donors in flow-through diffusion cells at 32°C over 24 hours (ethics: Kaunas Regional Biomedical Research Ethics Committee, BE-2-42). Menthol was quantified by validated GC/FID (R²=0.99996). Statistics: Mann-Whitney U test; Cohen's d.

Results: 3D printing produced a 4.4-fold higher epidermal menthol accumulation versus casting (22.0 vs 5.0 µg/mL; p=0.0004; Cohen's d=1.79). The epidermal-to-dermal ratio was markedly higher for 3D printing (0.230 vs 0.066), indicating preferential epidermal drug retention. Thickness uniformity CV was 7.3% for 3D printing versus 19.7% for casting; drug content RSD was 4.7% versus 9.5%. SEM of blank cast films showed smooth homogeneous surfaces, confirming that inferior precision in active formulations is attributable to menthol volatility during bulk drying rather than procedural deficiencies in the casting method itself.

Conclusions: Taken together, these results suggest 3D printing warrants further investigation as a manufacturing platform for natural terpene-based transdermal biomaterials, offering superior epidermal drug retention and manufacturing reproducibility.