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 (C18:1(n-9))-PG, linoleic acid (C18:2(n-6))-PG and alpha-linolenic acid (C18:3(n-3))-PG, mono- or di-esters, enhance the penetration of lidocaine relatively to the vehicle (without enhancer). The conjugates of oleic acid (C18:1(n-9)) and linoleic acid (C18:2(n-6)) with PG have demonstrated a similar enhancing effect as the corresponding free fatty acids. Interestingly, although the mono- or the di- conjugates of alpha-linolenic acid (C18:3(n-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 alpha-linolenic acid (C18:3(n-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 alpha-linolenic acid (C18:3(n-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.
Department of Pharmacology and School of Pharmacy, E.D. Bergmann Campus, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Shimon
S
Ben-Shabat
Nir
N
Baruch
Amnon C
AC
Sintov
D000818:Animals; D005231:Fatty Acids, Unsaturated / Q000737:chemistry* / Q000633:toxicity; D007509:Irritants / Q000633:toxicity*; D008012:Lidocaine / Q000008:administration & dosage / Q000737:chemistry; D019787:Linoleic Acid / Q000737:chemistry; D008297:Male; D019301:Oleic Acid / Q000737:chemistry; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry*; D011817:Rabbits; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D017962:alpha-Linolenic Acid / Q000737:chemistry
D005231:Fatty Acids, Unsaturated; D007509:Irritants; D017962:alpha-Linolenic Acid; D019301:Oleic Acid; D011092:Polyethylene Glycols; D008012:Lidocaine; D019787:Linoleic Acid