Conjugates of unsaturated fatty acids with propylene glycol as potentially less-irritant skin penetration enhancers

Fatty acids (FA) are well known as efficient enhancers for transdermal delivery of drugs; however, their frequent dermal toxicity limits their regular use. In order to utilize the fatty acid as a safe enhancer devoid of its irritant effect, we have synthesized and evaluated a series of fatty acids conjugated to propylene glycol (FA-PG). Each one of the conjugates was prepared as a mono- or di- acyl ester derivative. The effects of the synthetic enhancers on the porcine skin permeability were evaluated in a diffusion cell system using lidocaine as the model drug. In addition, in vivo examinations in rabbits were preformed for skin toxicological evaluation. The results indicate that among the FA-PG conjugates, oleic acid (C18:1n-9)-PG, linoleic acid (C18:2n-6)-PG and α-linolenic acid (C18:3n-3)-PG, mono- or di-esters, enhance the penetration of lidocaine relatively to the vehicle (without enhancer). The conjugates of oleic acid (C18:1n-9) and linoleic acid (C18:2n-6) with PG have demonstrated a similar enhancing effect as the corresponding free fatty acids. Interestingly, although the mono- or the di- conjugates of α-linolenic acid (C18:3n-3) with PG enhanced the lidocaine flux as the other two fatty acid conjugates, they resulted in a reduced permeability as compared to the action of their free acid. In addition, the mono-conjugates of α-linolenic acid (C18:3n-3) with PG exhibited elevated skin irritation in rabbits (relative to the fatty acid alone) compared to the significantly reduced irritation of oleate-PG and linoeate-PG mono-conjugates. In conclusion, except saturated FA-PG and α-linolenic acid (C18:3n-3) - PG mono-conjugates, unsaturated fatty acids (e.g., oleic and linoleic acids) after conjugation to PG may be safe and effective enhancers for delivering topical drugs.