A two-step design of experiments approach to investigate the simultaneous effects of ion-pairing and chemical enhancers to improve the permeability of lornoxicam in a topical hydrogel patch

A two-step experimental design was used to develop a lornoxicam (LOR)-loaded topical hydrogel patch. We specifically focused on the simultaneous effect of the ion pair formation agent (triethanolamine [TEA]) and the chemical enhancer (cremophor RH40 [RH40]) on flux and conducted physicochemical studies and skin physiology assessments to obtain further information.

Drug-in-adhesive patches were fabricated using a micrometer-adjustable film applicator. The applied Design of Experiments (DoE) approach consisted of the Fractional Factorial Resolution V + design and the Central Composite Face design established by the MODDE^® 12.0 software. Molecular-level drug-excipient interactions were investigated using infrared (IR) and proton nuclear magnetic resonance (¹H NMR) spectroscopy. The effects on skin physiological function was assessed using DermaLab Combo.

DoE results revealed that TEA enhanced flux by 3.14-fold, whereas RH40 reduced it by 4.62-fold. The addition of RH40 resulted in the disappearance of the proton peak within the region of 12–13 ppm, suggesting competition for hydrogen bonding with LOR between TEA and RH40. The optimized formulation (4% TEA, 0% RH40, and 0.2% Al(OH)₃) increased skin hydration by 6.20-fold. Opposing effects of TEA and RH40 on skin elasticity were observed.

Expected flux and adhesion strength for the optimized formulation were 7.18 µg·cm^–2·h^–1 and 11.79 mJ, respectively. Our understanding of the conflicting effects of TEA and RH40 has been advanced. The integrated use of the two-step DoE, physicochemical studies, and skin physiology assessments was proven to be effective in elucidating the simultaneous effects of different permeation-modifying strategies on patches, thus having substantial value for the successful execution of future research endeavors.