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.
Ben-Shabat
Shimon
S
Department of Pharmacology and School of Pharmacy, E.D. Bergmann Campus, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Baruch
Nir
N
Sintov
Amnon C
AC
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