Dimethylamino acid esters as biodegradable and reversible transdermal permeation enhancers: effects of linking chain length, chirality and polyfluorination
Language English Country United States Media print-electronic
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Adenine analogs & derivatives metabolism MeSH
- Alanine administration & dosage analogs & derivatives chemical synthesis pharmacology MeSH
- Administration, Cutaneous MeSH
- Time Factors MeSH
- Chemistry, Pharmaceutical MeSH
- Dimethylamines MeSH
- Dodecanol MeSH
- Electric Impedance MeSH
- Esterases metabolism 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: 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.
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