Impact of ester promoieties on transdermal delivery of ketorolac.
Different types of ketorolac ester prodrugs incorporating tert-butyl (KT), benzyl (KB), heptyl (KH), and diketorolac heptyl (DKH) promoieties were synthesized for the comparison of percutaneous penetration. The prodrugs were characterized according to their melting point, capacity factor, lipophilicity, solubility in 30% ethanol/buffer, enzymatic hydrolysis, in vitro skin permeation, hair follicle accumulation, and in vivo skin tolerance. Interactions between the prodrugs and esterases were predicted by molecular docking. Both equimolar suspensions and saturated solutions in 30% ethanol/pH 7.4 buffer were employed as the applied dose. All of the prodrugs exhibited a lower melting point than ketorolac. The lipophilicity increased in the following order: ketorolac < KT < KB < KH < DKH. The prodrugs were rapidly hydrolyzed to the parent drug in esterase medium, skin homogenate, and plasma, with KT and KB exhibiting higher degradation rates. KT exhibited the highest skin permeation, followed by KB. The flux of KT and KB exceeded that of ketorolac by 2.5-fold and twofold, respectively. KH and DKH did not improve ketorolac permeation but exhibited a sustained release behavior. KT and KH revealed selective absorption into follicles and a threefold greater follicular uptake compared with ketorolac. KB, KH, and DKH slightly but significantly increased transepidermal water loss (TEWL) after consecutive administration for 7 days, whereas ketorolac and KT exhibited no influence on TEWL. According to the experimental results, it can be concluded that an optimal balance between lipophilicity and aqueous solubility is important in the design of a successful prodrug. The acceptable skin tolerance for safe application is also an important consideration.
Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Kuo-Sheng
KS
Liu
Pei-Wen
PW
Hsieh
Ibrahim A
IA
Aljuffali
Yin-Ku
YK
Lin
Shu-Hao
SH
Chang
Jhi-Joung
JJ
Wang
Jia-You
JY
Fang
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D001711:Biotransformation; D004950:Esterases / Q000737:chemistry / Q000378:metabolism; D004951:Esterification; D005260:Female; D018859:Hair Follicle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D020910:Ketorolac / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012869:Skin Absorption; D012995:Solubility; D034421:Sus scrofa; D014018:Tissue Distribution; D057968:Transdermal Patch; D044366:Transition Temperature
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011355:Prodrugs; D004950:Esterases; D020910:Ketorolac
absorption; enzymology; ester prodrug; formulation; hydrolysis; ketorolac; percutaneous; promoiety; skin; transdermal delivery