title: l-Carvyl esters as penetration enhancers for the transdermal delivery of 5-fluorouracil.
abstract: To develop effective and safe penetration enhancers, a series of l-carvyl esters, namely, 5-isopropenyl-2-methylcyclohex-2-en-1-yl heptanoate (C-HEP), 5-isopropenyl-2- methylcyclohex-2-en-1-yl octanoate (C-OCT), 5-isopropenyl-2-methylcyclohex-2-en-1-yl decanoate (C-DEC), 5-isopropenyl-2-methylcyclohex-2-en-1-yl dodecanoate (C-DOD), 5-isopropenyl-2-methylcyclohex-2-en-1-yl tetradecanoate (C-TET), and 5-isopropenyl-2-methylcyclohex-2-en-1-yl palmitate (C-PAL), was synthesized from l-carveol and saturated fatty acids (C7-C16). The volatility of l-carveol and l-carvyl esters was evaluated by a live weight loss experiment. The enhancing effects of l-carvyl esters on 5-fluorouracil (FU) were investigated in the in vitro permeation experiment on rat skin. The stratum corneum (SC) uptakes of the enhancers were tested in vitro by gas chromatography. Only the l-carvyl esters with a moderate SC uptake, namely, C-OCT (C8), C-DEC (C10), and C-DOD (C12), showed a potential to enhance FU skin permeation. An evident parabolic relationship was found between the permeation enhancement of FU and the SC uptake of the l-carvyl esters. The l-carvyl esters with a chain length of C8-C12 seemed to be favorable for FU.
authors.affiliation: Department of Pharmaceutical Sciences, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning 110016, People's Republic of China.
authors.forename: Manli
authors.initials: M
authors.lastname: Wang
authors.forename: Honglei
authors.initials: H
authors.lastname: Xi
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cun
authors.forename: Yang
authors.initials: Y
authors.lastname: Chen
authors.forename: Yongnan
authors.initials: Y
authors.lastname: Xu
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D002626:Chemistry, Pharmaceutical; D002849:Chromatography, Gas; D000081005:Cyclohexane Monoterpenes; D004952:Esters / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D039821:Monoterpenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010539:Permeability; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013678:Technology, Pharmaceutical / Q000379:methods; D014835:Volatilization
chemical_list: D000964:Antimetabolites, Antineoplastic; D000081005:Cyclohexane Monoterpenes; D004952:Esters; D005227:Fatty Acids; D039821:Monoterpenes; C075856:carveol; D005472:Fluorouracil
references.citation: J Pharm Sci. 2004 Jun;93(6):1415-30
references.pmid: 15124201
references.citation: Nat Biotechnol. 2008 Nov;26(11):1261-8
references.pmid: 18997767
references.citation: Bioorg Med Chem. 2003 Dec 1;11(24):5381-90
references.pmid: 14642582
references.citation: Acta Derm Venereol. 1997 Jul;77(4):264-7
references.pmid: 9228215
references.citation: Mol Pharm. 2010 Aug 2;7(4):1266-73
references.pmid: 20545350
references.citation: Int J Pharm. 2008 Mar 20;352(1-2):92-103
references.pmid: 18053661
references.citation: J Pharm Pharmacol. 1996 Nov;48(11):1133-7
references.pmid: 8961160
references.citation: J Pharm Sci. 2011 Aug;100(8):3186-3195
references.pmid: 21416467
references.citation: Int J Pharm. 2005 Nov 23;305(1-2):2-12
references.pmid: 16246513
references.citation: Skin Pharmacol Physiol. 2006;19(2):106-21
references.pmid: 16685150
references.citation: Eur J Pharm Biopharm. 2008 May;69(1):199-213
references.pmid: 18065216
references.citation: Adv Drug Deliv Rev. 2004 Mar 27;56(5):603-18
references.pmid: 15019749
references.citation: Pharm Res. 1991 Jan;8(1):17-24
references.pmid: 2014203
references.citation: Eur J Pharmacol. 2012 Aug 5;688(1-3):1-5
references.pmid: 22200629
references.citation: Food Chem Toxicol. 2008 Nov;46 Suppl 11:S88-90
references.pmid: 18640177
references.citation: Int J Pharm. 2012 Dec 15;439(1-2):260-8
references.pmid: 23000063
references.citation: Curr Drug Deliv. 2011 Jul;8(4):456-73
references.pmid: 21453254
references.citation: J Pharm Sci. 2009 Mar;98(3):926-44
references.pmid: 18623209