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
• Adenine analogs & derivatives   metabolism   MeSH
• Alanine administration & dosage   analogs & derivatives   chemical synthesis   pharmacology   MeSH
• Administration, Cutaneous MeSH
• Time Factors MeSH
• Dimethylamines MeSH
• Dodecanol MeSH
• Electric Impedance MeSH
• Esterases metabolism   MeSH
• Chemistry, Pharmaceutical MeSH
• Halogenation MeSH
• Hydrocortisone metabolism   MeSH
• Hydrolysis MeSH
• Indomethacin metabolism   MeSH
• Isomerism MeSH
• Caproates administration & dosage   chemical synthesis   pharmacology   MeSH
• Skin Absorption drug effects   MeSH
• Skin drug effects   metabolism   MeSH
• Methylamines administration & dosage   chemical synthesis   pharmacology   MeSH
• Molecular Structure MeSH
• Drug Carriers MeSH
• Organophosphonates metabolism   MeSH
• Swine MeSH
• Drug Compounding MeSH
• Drug Stability MeSH
• Theophylline metabolism   MeSH
• Structure-Activity Relationship MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• adefovir MeSH Browser
• Adenine MeSH
• Alanine MeSH
• Dimethylamines MeSH
• dodecyl 2-(N,N-dimethylamino)propionate MeSH Browser
• dodecyl 6-(dimethylamino)hexanoate MeSH Browser
• Dodecanol MeSH
• Esterases MeSH
• Hydrocortisone MeSH
• Indomethacin MeSH
• Caproates MeSH
• Methylamines MeSH
• Drug Carriers MeSH
• Organophosphonates MeSH
• Theophylline 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
• Aminocaproates MeSH
• Administration, Cutaneous MeSH
• Butyrates administration & dosage   metabolism   MeSH
• Diffusion Chambers, Culture MeSH
• Esterases analysis   MeSH
• Griseofulvin administration & dosage   metabolism   MeSH
• Carbamates chemical synthesis   pharmacology   MeSH
• Clotrimazole administration & dosage   metabolism   MeSH
• Skin Absorption MeSH
• Skin drug effects   metabolism   MeSH
• Aminocaproic Acid chemical synthesis   pharmacology   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Permeability MeSH
• Aged MeSH
• Theophylline administration & dosage   metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Aminocaproates MeSH
• Butyrates MeSH
• dodecyl 6-aminocaproate MeSH Browser
• Esterases MeSH
• flobufen MeSH Browser
• Griseofulvin MeSH
• Carbamates MeSH
• Clotrimazole MeSH
• Aminocaproic Acid MeSH
• Theophylline MeSH
• transkarbam 12 MeSH Browser