Biodegradable derivatives of tranexamic acid as transdermal permeation enhancers KaterˇinaVa ´vrova ´ a, * , Alexandr Hraba ´lek a , Pavel Dolez ˇal b , Toma ´s ˇ Holas a , Jana Klimentova ´ a a Department of Inorganic and Organic Chemistry, Charles University, Faculty of Pharmacy, Heyrovske ´ho 1203, 500 05 Hradec Kra ´love ´, Czech Republic b Department of Pharmaceutical Technology, Charles University, Faculty of Pharmacy, Heyrovske ´ho 1203, 500 05 Hradec Kra ´love ´, Czech Republic Received 2 August 2004; accepted 18 January 2005 Available online 17 February 2005 Abstract The purpose of this work was to develop a novel approach to transdermal permeation enhancer design, based on utilizing some favorable properties of their metabolites. As an example of this concept, a series of carbamic acid salts of tranexamic acid (TXA) esters was synthesized, because TXA was previously shown to improve skin barrier homeostasis. Enhancement activities of 1% TXA derivatives dispersed in both hydrophilic and lipophilic vehicles were evaluated in vitro using human skin and theophylline as a model drug. Dispersed in an aqueous donor vehicle, the dodecyl ester showed the enhancement ratio (ER) of 4.3F0.9, which is almost 2 times higher than that of 1-dodecylazepan-2-one (Azone; 2.2F0.7). From an isopropyl-myristate suspension, the decyl ester was the most effective enhancer (4.9F1.4), while Azone was inactive. Decomposition of the carbamate in a slightly acidic environment was shown by FTIR; hydrolysis of the pertinent ester by porcine esterase was monitored by TLC and HPLC. Biodegradable enhancers of this type could mediate easier and faster recovery of the skin barrier after transdermal delivery through the action of the released TXA. D 2005 Elsevier B.V. All rights reserved. Keywords: Transdermal; Permeation enhancer; Tranexamic acid derivatives; Enzymatic degradability 1. Introduction One of the approaches towards broadening the array of drugs that can be delivered transdermally is the use of permeation enhancers. Enhancers can act on the stratum corneum intracellular keratin, influence desmosomes, modify the intercellular lipid domains or alter the solvent nature of the stratum corneum to decrease the skin barrier resistance [1]. Although a number of chemically different compounds have been reported as permeation enhancers, none of them has the ideal properties described by Barry [2]. 0168-3659/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.jconrel.2005.01.002 T Corresponding author. Tel.: +420 495 067 497; fax: +420 495 514 330. E-mail address: vavrovak@faf.cuni.cz (K. Va ´vrova ´). Journal of Controlled Release 104 (2005) 41 – 49 www.elsevier.com/locate/jconrel