Understanding Drug Skin Permeation Enhancers Using Molecular Dynamics Simulations.

Area of Science:

• Pharmacology
• Biophysics
• Materials Science

Background:

• The skin's permeability barrier restricts transdermal drug delivery.
• Chemical permeation enhancers (PEs) are used to improve drug skin permeability in topical formulations.
• Current in vitro methods measure net effects but lack molecular insights into PE-skin interactions, hindering rational formulation design.

Purpose of the Study:

• To investigate the effects of various PEs on the transdermal transport of metronidazole, caffeine, and naproxen.
• To elucidate the molecular mechanisms underlying PE interactions with the skin barrier.
• To develop a computational model for predicting PE efficacy in topical drug formulation.

Main Methods:

• Atomistic molecular dynamics (MD) simulations were employed to model 11 PE-containing formulations.
• Calculated free energy differences between formulations and the skin barrier to determine PE concentration in the skin.
• Utilized modified barrier structures to compute PE permeability enhancement ratios (ERs) for specific drugs.

Main Results:

• MD simulations successfully reproduced the ranking of PEs based on their enhancement ratios (ERs).
• A root-mean-square error (RMSE) of 0.58 log units was achieved for calculated partition coefficients.
• Quantitative correlation with experimental data requires further refinement due to measurement variability.

Conclusions:

• MD simulations provide valuable insights into the molecular mechanisms of permeation enhancement.
• The developed model offers a promising approach for the rational design of topical drug formulations.
• Further refinement of computational models is needed for precise quantitative prediction of transdermal drug transport.