Understanding the Structure-Release Relationships of Sepineo™: molecular dynamics, physico-chemical characterization, in vitro and ex vivo permeation
Abstract
The physical and mechanical characteristics of gels are crucial in developing and manufacturing various topical therapeutic products. This study thoroughly examined the influence of pH modifications and the ionization status of diclofenac sodium, as an Active Pharmaceutical Ingredient (API), on the rheological behavior, in vitro release kinetics, and ex vivo skin permeation profiles of Sepineo™ gels. Further, molecular dynamic simulations were conducted to elucidate the relationship between the ionization status of the API and its interactions with the components of Sepineo™ gels across different pH levels, specifically focusing on the pKa value of diclofenac sodium (pKa 3.84).
To evaluate the impact of pH changes and diclofenac ionization, four different Sepineo™ (3 wt%) gels loaded with diclofenac sodium (0 wt%, 0.1 wt% or 1 wt%) were prepared at different pH conditions (2.55, 7.4 and 11.56, respectively). As pH shifted from acidic to basic conditions, a change in the stiffness of Sepineo gels was observed, irrespective of the small amount of diclofenac sodium. The elasticity behaviour was affected by these changes in the pH when the formulations were loaded with 0.1 and 1 wt% of diclofenac sodium. The ex vivo permeation analysis of diclofenac from 0.1 wt% gel formulations across pig ear skin was performed, with the expectation that fully ionized diclofenac would permeate poorly. Interestingly, despite being diclofenac fully ionized, formulations at a pH value of 11.56 showed decreased drug permeation through the skin in comparison to the formulations at pH 7.4.
These data suggest that the interaction between drug and gel components was more influenced by the pH of the formulation rather than by the ionization status of the API. Further permeation tests showed that drug permeation across the skin was influenced not only by pH but also by the interactions between the drug and the polymer matrix itself. Overall, we found that the pH of the formulation, rather than its rheological properties, could significantly affect drug release and permeation profiles. Through the combination of several characterizations, it was possible to rationalize the relationship between the drug permeation and the physico-chemical properties of the gel formulations.
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Materials
The formulation of the gel was designed using the following materials: Diclofenac Sodium (Sigma Aldrich, Singapore) as the API chosen for its potent anti-inflammatory and pain-relieving properties. Sepineo P600, acquired from Seppic, was selected as the gelling agent due to its exceptional ability to create a stable and homogenous gel matrix, essential for controlled drug release.
Ayça Altay Benetti, Harshvardhan Modh, Tomasz Panczyk, Abu Zayed Badruddoza, Jaymin Shah, Matthias Gerhard Wacker, Giorgia Pastorin, Understanding the Structure-Release Relationships of Sepineo™: molecular dynamics, physico-chemical characterization, in vitro and ex vivo permeation, Journal of Drug Delivery Science and Technology,
2025, 106957, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.106957.
Read also our introduction article on Topical Excipients here:
