In-Silico Modelling of Transdermal Delivery of Macromolecule Drugs Assisted by a Skin Stretching Hypobaric Device

Abstract

Objectives To develop a simulation model to explore the interplay between mechanical stretch and diffusion of large molecules into the skin under locally applied hypobaric pressure, a novel penetration enhancement method. Methods Finite element method was used to model the skin mechanical deformation and molecular diffusion processes, with validation against in-vitro transdermal permeation experiments. Simulations and experimental data were used together to investigate the transdermal permeation of large molecules under local hypobaric pressure. Results Mechanical simulations resulted in skin stretching and thinning (20%–26% hair follicle diameter increase, and 21%–27% skin thickness reduction). Concentration of dextrans in the stratum corneum was below detection limit with and without hypobaric pressure. Concentrations in viable epidermis and dermis were not affected by hypobaric pressure (approximately 2 μg $$\bullet$$ ∙ cm−2). Permeation into the receptor fluid was substantially enhanced from below the detection limit at atmospheric pressure to up to 6 μg $$\bullet$$ ∙ cm−2 under hypobaric pressure. The in-silico simulations compared satisfactorily with the experimental results at atmospheric conditions. Under hypobaric pressure, satisfactory comparison was attained when the diffusion coefficients of dextrans in the skin layers were increased from $$\sim$$ ∼ 10 μm2$$\bullet$$ ∙ s−1 to between 200–500 μm2$$\bullet$$ ∙ s−1. Conclusions Application of hypobaric pressure induces skin mechanical stretching and enlarges the hair follicle. This enlargement alone cannot satisfactorily explain the increased transdermal permeation into the receptor fluid under hypobaric pressure. The results from the in-silico simulations suggest that the application of hypobaric pressure increases diffusion in the skin, which leads to improved overall transdermal permeation.

Avances en modelos in silico para el descubrimiento rápido de fármacos: transformando la farmacología computacional

“…La interacción entre el modelado in silico y los métodos experimentales facilitó la identificación de candidatos a fármacos con propiedades mejoradas, destacando el potencial de esta estrategia integrada en el proceso de descubrimiento de fármacos (Tawada, 2023). Sebastia-Saez et al (2023), presentan un caso de estudio sobre el modelado in silico de la entrega transdérmica de fármacos macromoleculares asistida por un dispositivo hiperbárico de estiramiento de la piel. Este trabajo destaca cómo los modelos in silico pueden ser utilizados para predecir y optimizar la entrega de fármacos, complementando los experimentos in vitro e in vivo para evaluar la eficacia de los sistemas de entrega de fármacos.…”

In Silico Study on the Contribution of the Follicular Route to Dermal Permeability of Small Molecules

“…Here, we use a recently reported 2-D mechanistic in silico skin permeation mathematical model. The model has been validated recently in the literature for a variety of cases [8,9]. This methodology allows carrying out a study for a set of chemical compounds and examining the effects of the parameters involved.…”

“…mechanistic mathematical model used in this work consists in a 2-D geometric representation of the skin layers, complemented with state-of-the-art QSPRs to calculate the diffusion and partition coefficients. The model is an adaptation of a previously published model[8,9], to accommodate a configuration with an infinite dose in the vehicle and a sink in the receiver, used frequently in skin permeability lab work. Dimensions and boundary layers are represented in Fig.1for an open FR.…”