Effect of fatty acids on the transdermal delivery of donepezil: in vitro and in vivo evaluation.
The effect of fatty acids on the skin permeation of donepezil base (DPB) and its hydrochloride salt (DPH) were studied in vitro using hairless mouse and human cadaver skin. DPB and DPH were solubilized in propylene glycol (PG) containing 1% (w/v) fatty acid, after which the in vitro permeation through hairless mouse skin and human cadaver skin were evaluated using Keshary-Chien diffusion cells. The optimized formulation obtained from the in vitro study was then tested in rats for an in vivo pharmacokinetic study. The relative in vitro skin permeation rate of donepezil (DP) through the hairless mouse skin showed a parabolic relationship with increased carbon length of the fatty acid enhancers. Among the fatty acids tested, oleic acid for DPB and palmitoleic acid for DPH showed the highest enhancing effect, respectively. Both the permeation rates of DPB and DPH evaluated in human cadaver skin were in good correlation with those in hairless mouse skin, regardless of the presence of fatty acids. This suggests that the mouse skin model serves as a useful in vitro system that satisfactorily represents the characteristics of the human skin. Moreover, based on the in vitro results, the optimal formulation that could maintain the human plasma concentration of 50 ng/mL was determined to be 10mg DP with 1% (w/v) enhancer. When the DP transdermal formulations were applied to the abdominal skin of rats (2.14 cm(2)), the C(ss) was maintained for 48 h, among which the highest value of 52.21 ± 2.09 ng/mL was achieved with the DPB formulation using oleic acid. These results showed that fatty acids could enhance the transdermal delivery of DP and suggested the feasibility of developing a novel transdermal delivery system for clinical use.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea.
Joonho
J
Choi
Min-Koo
MK
Choi
Saeho
S
Chong
Suk-Jae
SJ
Chung
Chang-Koo
CK
Shim
Dae-Duk
DD
Kim
D000279:Administration, Cutaneous; D000818:Animals; D002102:Cadaver; D002626:Chemistry, Pharmaceutical; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D007189:Indans / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D019301:Oleic Acid / Q000008:administration & dosage* / Q000737:chemistry; D010539:Permeability; D010880:Piperidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019946:Propylene Glycol / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013678:Technology, Pharmaceutical / Q000379:methods
D002800:Cholinesterase Inhibitors; D005229:Fatty Acids, Monounsaturated; D007189:Indans; D010880:Piperidines; D012997:Solvents; C008757:palmitoleic acid; D019301:Oleic Acid; D019946:Propylene Glycol; D000077265:Donepezil