Niacinamide (NIA) is a cornerstone ingredient in dermatology, valued for its ability to reduce transepidermal water loss (TEWL), improve skin elasticity, and manage inflammatory conditions like acne and rosacea. However, achieving efficient transdermal delivery of NIA is difficult because its hydrophilic nature limits its ability to partition into the lipid-rich stratum corneum (SC), the skin’s primary barrier. While researchers have explored chemical penetration enhancers, the impact of donor phase pH—specifically how shifting from the skin’s natural “acid mantle” (pH 5.0) to a neutral state (pH 7.4) affects the barrier—remains under-researched. This study considers pH modulation as a potential solution, hypothesizing that pH-driven changes in SC lipid organization can reversibly enhance NIA permeability by creating localized structural microdefects in the lipid matrix.
Methods
Researchers conducted Franz cell diffusion experiments using both full-thickness human skin and 3D reconstructed epidermal tissue (EpiDerm) to measure NIA permeation over 24 to 48 hours. Electrical Impedance Spectroscopy (EIS) was simultaneously employed to characterize the skin’s electrical properties, specifically membrane resistance (Rmem) and effective capacitance (Ceff). NIA and its potential microbial metabolite, nicotinic acid, were quantified using HPLC-UV and GC-MS, while pH switch experiments were utilized to assess the reversibility of the observed effects.
Key Findings
- Enhanced Permeation: Neutral donor pH (7.4) increased NIA skin permeation by approximately twofold compared to acidic pH (5.0) in both human skin and reconstructed tissue models.
- Structural Alterations: Exposure to pH 7.4 significantly decreased membrane resistance (Rmem) and increased effective capacitance (Ceff), indicating more open transport pathways and changes in the dielectric behavior of the SC.
- Reversible Lipid Modulation: The effects were found to be reversible, likely stemming from the partial deprotonation of free fatty acids in the SC lipid domains, which introduces temporary microdefects that facilitate transport.
- Porous-Pathway Correlation: A clear inverse relationship was found between NIA permeability and electrical resistance, suggesting that NIA transport partially follows an aqueous pore pathway influenced by changes in porosity and tortuosity.
- Microbial Metabolism: During prolonged exposure (>24 hours), skin-associated microbes began converting NIA into nicotinic acid (NA), an effect that was successfully inhibited by the bacteriostatic agent sodium azide.
This research provides a novel mechanistic understanding of how donor pH acts as a critical regulator of skin permeability by modulating the ionization state of SC lipids rather than merely altering the drug’s solubility. By establishing that neutral pH is a mild and reversible strategy for enhancing NIA delivery, the study offers significant future implications for the design of topical formulations, such as patches or masks, where pH control can be used to optimize efficacy. Furthermore, the discovery of microbiota-mediated transformation of NIA highlights a vital new consideration for scientists evaluating the long-term safety and performance of skincare products.
Link to the study: https://www.nature.com/articles/s41598-026-41992-4
In the image: Effect of pH on the electrical skin membrane properties. (A) Relative changes in membrane resistance (∆Rmem) and (B) effective capacitance (∆Ceff) for full-thickness human skin membranes (donors 1–3) and the EpiDerm tissue models following 24 h exposure of pH 7.4 (PBS) or pH 5.0 (CBS) conditions. Boxes represent the interquartile range with medians shown as horizontal lines. Number of replicates: human skin, n = 8 (pH 5.0) and n = 17 (pH 7.4); EpiDerm, n = 7 (pH 5.0) and n = 4 (pH 7.4).