Thiomenthol derivatives as novel percutaneous absorption enhancers

Area of Science:

• Pharmacology
• Dermatology
• Medicinal Chemistry

Background:

• Percutaneous absorption of drugs is crucial for topical and transdermal delivery.
• Hydrogels offer a promising vehicle for drug delivery but often face challenges with drug penetration.
• Thiomenthol derivatives are explored as potential enhancers for drug delivery systems.

Purpose of the Study:

• To synthesize novel thiomenthol derivatives.
• To evaluate their efficacy in promoting percutaneous absorption of ketoprofen from hydrogels in rats.
• To investigate the relationship between physicochemical properties of these derivatives and their enhancing activity and skin irritancy.

Main Methods:

• Synthesis of thiomenthol derivatives.
• In vivo evaluation of ketoprofen percutaneous absorption using a rat model.
• Pharmacokinetic analysis to determine apparent penetration rate (Rp) and enhancement factor (Ef).
• Microscopic assessment of skin irritancy (Total Irritation Score, TIS).
• Calculation of physicochemical parameters (log P, steric energy) and multiple regression analysis.

Main Results:

• Thiomenthol derivatives significantly enhanced ketoprofen absorption from hydrogels.
• An enhancement factor (Ef) was established to quantify the promoting activity.
• Skin irritancy was evaluated, and a Total Irritation Score (TIS) was determined.
• A parabolic relationship was observed between the partition coefficient (log P) and both enhancement factor (Ef) and Total Irritation Score (TIS).

Conclusions:

• Thiomenthol derivatives are effective enhancers for ketoprofen percutaneous absorption from hydrogels.
• Physicochemical properties, particularly log P, play a significant role in both the efficacy and safety profile of these enhancers.
• The findings suggest that optimizing enhancer design based on log P can lead to improved drug delivery with minimized skin irritation.