Dimethylamino acid esters as biodegradable and reversible transdermal permeation enhancers: effects of linking chain length, chirality and polyfluorination.
OBJECTIVE
Series of N,N-dimethylamino acid esters was synthesized to study their transdermal permeation-enhancing potency, biodegradability and reversibility of action. Effects of chirality, linking chain length and polyfluorination were investigated.


METHODS
In vitro activities were evaluated using porcine skin and four model drugs-theophylline, hydrocortisone, adefovir and indomethacin. Biodegradability was determined using porcine esterase, reversibility was measured using electrical resistance.


RESULTS
No differences in activity were found between (R), (S) and racemic dodecyl 2-(dimethylamino)propanoate (DDAIP). Substitution of hydrocarbon tail by fluorocarbon one resulted in loss of activity. Replacement of branched linking chain between nitrogen and ester of DDAIP by linear one markedly improved penetration-enhancing activity with optimum in 4-6C acid derivatives. Dodecyl 6-(dimethylamino)hexanoate (DDAK) was more potent than clinically used skin absorption enhancer DDAIP for theophylline (enhancement ratio of DDAK and DDAIP was 17.3 and 5.9, respectively), hydrocortisone (43.2 and 11.5) and adefovir (13.6 and 2.8), while DDAIP was better enhancer for indomethacin (8.7 and 22.8). DDAK was rapidly metabolized by porcine esterase, and displayed low acute toxicity. Electrical resistance of DDAK-treated skin barrier promptly recovered to control values.


CONCLUSIONS
DDAK, highly effective, broad-spectrum, biodegradable and reversible transdermal permeation enhancer, is promising candidate for future research.
Novotný
Jakub
J
Centre for New Antivirals and Antineoplastics, Department of Inorganic and Organic Chemistry, Faculty of Pharmacy Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05, Hradec Králové, Czech Republic.
Kovaríková
Petra
P
Novotný
Michal
M
Janůsová
Barbora
B
Hrabálek
Alexandr
A
Vávrová
Katerina
K
D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000279:Administration, Cutaneous; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002208:Caproates / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D004123:Dimethylamines; D007851:Dodecanol; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D017097:Electric Impedance; D004950:Esterases / Q000378:metabolism; D054879:Halogenation; D006854:Hydrocortisone / Q000378:metabolism; D006868:Hydrolysis; D007213:Indomethacin / Q000378:metabolism; D007536:Isomerism; D008744:Methylamines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D015394:Molecular Structure; D063065:Organophosphonates / Q000378:metabolism; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013552:Swine; D013806:Theophylline / Q000378:metabolism; D013997:Time Factors
D002208:Caproates; D004123:Dimethylamines; D004337:Drug Carriers; D008744:Methylamines; D063065:Organophosphonates; C534415:dodecyl 6-(dimethylamino)hexanoate; D007851:Dodecanol; C085388:dodecyl 2-(N,N-dimethylamino)propionate; C053001:adefovir; D013806:Theophylline; D004950:Esterases; D000225:Adenine; D000409:Alanine; D006854:Hydrocortisone; D007213:Indomethacin