Human Skin Permeation Enhancement Using PLGA Nanoparticles Is Mediated by Local pH Changes

Area of Science:

• Pharmaceutical Sciences
• Biomaterials Science
• Dermatology

Background:

• Optimizing transdermal drug delivery is a significant pharmaceutical challenge.
• Poly(lactide-co-glycolide) (PLGA) nanoparticles are investigated for their potential in drug permeation enhancement.
• Flufenamic acid (FFA) is an anti-inflammatory drug used as a model compound.

Purpose of the Study:

• To investigate the influence of PLGA nanoparticles on the dermal permeation of flufenamic acid (FFA).
• To evaluate the role of vehicle pH and skin models in FFA permeation.
• To elucidate the mechanism behind enhanced dermal permeation mediated by PLGA nanoparticles.

Main Methods:

• Permeation experiments using static Franz diffusion cells under infinite dosing conditions.
• Testing with drug-free and drug-loaded PLGA nanoparticles in various vehicles (buffered and non-buffered).
• Utilizing human epidermis and reconstructed human epidermis equivalents as skin models.
• Employing pH-sensitive fluorescent probes to visualize pH changes around nanoparticles.

Main Results:

• Both drug-free and drug-loaded PLGA nanoparticles significantly increased FFA permeation across the skin.
• Buffered vehicles demonstrated the impact of pH on FFA permeation.
• Localized pH decrease during PLGA nanoparticle hydrolytic degradation was observed and visualized.
• Enhanced permeation was not attributed to hair follicles.
• Permeation of caffeine, a weak base, was unaffected, supporting the pH-mediated mechanism.

Conclusions:

• PLGA nanoparticles enhance the dermal permeation of flufenamic acid.
• The enhanced permeation is primarily mediated by a localized decrease in pH due to the hydrolytic degradation of PLGA nanoparticles.
• This mechanism is independent of hair follicle contribution and specific to the drug's properties (weak acid).