Ketorolac amide prodrugs for transdermal delivery: stability and in vitro rat skin permeation studies.
Various amide prodrugs of ketorolac were synthesized and their rat skin permeation characteristics were determined. The solubility of the prodrugs in propylene glycol (PG) was determined at 37 degrees C while lipophilicity was obtained as 1-octanol/water partition coefficient (logP) and capacity factor (k') using HPLC. Stability of the prodrugs in rat skin homogenate, plasma and liver homogenate was investigated to observe the enzymatic degradation. Rat skin permeation characteristics of the prodrugs saturated in PG were investigated using the Keshary-Chien permeation system at 37 degrees C. The logP value of the prodrugs increased up to 4.28 with the addition of various alkyl chain to ketorolac which has a logP of 1.04. Good linear relationship between logP and capacity factor was observed (r(2)=0.89). Amide prodrugs were converted to ketorolac only in rat liver homogenate. However, the skin permeation rate of amide prodrugs did not significantly increase, probably due to their low aqueous solubility. Chemical modification of the ketorolac amide prodrug and/or the selection of proper vehicle to increase aqueous solubility would be necessary for an effective transdermal delivery of ketorolac.
Kim
Bo-Yeon
BY
College of Pharmacy, Pusan National University, Pusan 609-735, South Korea.
Doh
Hea-Jeong
HJ
Le
Thanh Nguyen
TN
Cho
Won-Jea
WJ
Yong
Chul-Soon
CS
Choi
Han-Gon
HG
Kim
Jung Sun
JS
Lee
Chi-Ho
CH
Kim
Dae-Duk
DD
D000279:Administration, Cutaneous; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D066298:In Vitro Techniques; D020910:Ketorolac / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology*
D011355:Prodrugs; D020910:Ketorolac