PURPOSE: 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. MATERIALS AND 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. CONCLUSION: DDAK, highly effective, broad-spectrum, biodegradable and reversible transdermal permeation enhancer, is promising candidate for future research.

• MeSH
• adenin analogy a deriváty   metabolismus   MeSH
• alanin aplikace a dávkování   analogy a deriváty   chemická syntéza   farmakologie   MeSH
• aplikace kožní MeSH
• časové faktory MeSH
• chemie farmaceutická MeSH
• dimethylaminy MeSH
• dodekanol MeSH
• elektrická impedance MeSH
• esterasy metabolismus   MeSH
• halogenace MeSH
• hydrokortison metabolismus   MeSH
• hydrolýza MeSH
• indomethacin metabolismus   MeSH
• isomerie MeSH
• kapronáty aplikace a dávkování   chemická syntéza   farmakologie   MeSH
• kožní absorpce účinky léků   MeSH
• kůže účinky léků   metabolismus   MeSH
• methylaminy aplikace a dávkování   chemická syntéza   farmakologie   MeSH
• molekulární struktura MeSH
• nosiče léků MeSH
• organofosfonáty metabolismus   MeSH
• prasata MeSH
• příprava léků MeSH
• stabilita léku MeSH
• theofylin metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• adefovir MeSH Prohlížeč
• adenin MeSH
• alanin MeSH
• dimethylaminy MeSH
• dodecyl 2-(N,N-dimethylamino)propionate MeSH Prohlížeč
• dodecyl 6-(dimethylamino)hexanoate MeSH Prohlížeč
• dodekanol MeSH
• esterasy MeSH
• hydrokortison MeSH
• indomethacin MeSH
• kapronáty MeSH
• methylaminy MeSH
• nosiče léků MeSH
• organofosfonáty MeSH
• theofylin MeSH

PURPOSE: 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. CONCLUSION: 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.

• MeSH
• aminokapronáty MeSH
• aplikace kožní MeSH
• butyráty aplikace a dávkování   metabolismus   MeSH
• difuzní komory kultivační MeSH
• esterasy analýza   MeSH
• griseofulvin aplikace a dávkování   metabolismus   MeSH
• karbamáty chemická syntéza   farmakologie   MeSH
• klotrimazol aplikace a dávkování   metabolismus   MeSH
• kožní absorpce MeSH
• kůže účinky léků   metabolismus   MeSH
• kyselina 6-aminokapronová chemická syntéza   farmakologie   MeSH
• lidé MeSH
• molekulární struktura MeSH
• permeabilita MeSH
• senioři MeSH
• theofylin aplikace a dávkování   metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aminokapronáty MeSH
• butyráty MeSH
• dodecyl 6-aminocaproate MeSH Prohlížeč
• esterasy MeSH
• flobufen MeSH Prohlížeč
• griseofulvin MeSH
• karbamáty MeSH
• klotrimazol MeSH
• kyselina 6-aminokapronová MeSH
• theofylin MeSH
• transkarbam 12 MeSH Prohlížeč