Synthesis and enhancing effect of transkarbam 12 on the transdermal delivery of theophylline, clotrimazole, flobufen, and griseofulvin.
OBJECTIVE
Dodecyl-6-aminohexanoate (DDEAC) is a transdermal permeation enhancer with excellent activity, low toxicity, and no dermal irritation. We hypothesized that DDEAC reacts with air CO2 to form a two-chain ammonium carbamate--Transkarbam 12 (T12)--which is responsible for the enhancing effect.


METHODS
DDEAC and T12 were synthesized, their structures were confirmed by spectral methods, and their enhancing activity was studied using the Franz diffusion cell and human skin. A high-performance liquid chromatography method was developed for determination of T12, and its biodegradability was evaluated using porcine esterase.


RESULTS
Only the carbamate salt T12 was responsible for the high enhancing activity; DDEAC tested under argon to avoid reaction with CO2 was inactive. T12 enhanced transdermal permeation of drugs covering a wide range of physicochemical properties, including theophylline (enhancement ratio up to 55.6), clotrimazole (7.7), flobufen (5.0), and griseofulvin (24). The activity was pH-dependent, further confirming the importance of the carbamate structure. The metabolization of T12 followed a second-order kinetics with t(1/2) = 31 min.


CONCLUSIONS
Our results indicate that T12 is a promising biodegradable permeation enhancer for a wide range of drugs, and the structurally novel group of carbamate enhancers warrants further investigation.
Hrabálek
Alexandr
A
Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 50012 Hradec Králové, Czech Republic. Alexandr.Hrabalek@faf.cuni.cz
Dolezal
Pavel
P
Vávrová
Katerina
K
Zbytovská
Jarmila
J
Holas
Tomás
T
Klimentová
Jana
J
Novotný
Jakub
J
D000279:Administration, Cutaneous; D000368:Aged; D000614:Aminocaproates; D015119:Aminocaproic Acid / Q000138:chemical synthesis / Q000494:pharmacology; D002087:Butyrates / Q000008:administration & dosage / Q000378:metabolism*; D002219:Carbamates / Q000138:chemical synthesis / Q000494:pharmacology*; D003022:Clotrimazole / Q000008:administration & dosage / Q000378:metabolism*; D015194:Diffusion Chambers, Culture; D004950:Esterases / Q000032:analysis; D005260:Female; D006118:Griseofulvin / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D008297:Male; D015394:Molecular Structure; D010539:Permeability; D012867:Skin / Q000187:drug effects* / Q000378:metabolism; D012869:Skin Absorption; D013806:Theophylline / Q000008:administration & dosage / Q000378:metabolism*
D000614:Aminocaproates; D002087:Butyrates; D002219:Carbamates; C492029:transkarbam 12; C056474:flobufen; D006118:Griseofulvin; C083307:dodecyl 6-aminocaproate; D013806:Theophylline; D004950:Esterases; D003022:Clotrimazole; D015119:Aminocaproic Acid