Synthesis and in vitro evaluation of aminoacyloxyalkyl esters of 2-(6-methoxy-2-naphthyl)propionic acid as novel naproxen prodrugs for dermal drug delivery.
OBJECTIVE
To synthesize and evaluate various novel aminoacyloxyalkyl esters of naproxen (3a-i) and naproxenoxyalkyl diesters of glutamic and aspartic acids (3j-m) as potential dermal prodrugs of naproxen.


METHODS
The prodrugs 3a-m were synthesized, and their aqueous solubilities, lipophilicities and hydrolysis rates were determined in a buffered solution and in human serum. The permeation of selected prodrugs across excised postmortem human skin was studied in vitro.


RESULTS
The aminoacyloxyalkyl prodrugs showed higher aqueous solubilities and similar lipid solubilities, in terms of octanol-buffer partition coefficients (log Papp) at pH 5.0, when compared with naproxen. At pH 7.4 the prodrugs were significantly more lipophilic than naproxen. Prodrugs 3a-i showed moderate chemical stability in aqueous solutions at pH 5.0 and were rapidly converted to naproxen in human serum (t1/2 = 4-19 min). The selected aminoacyloxyalkyl prodrugs possessed a higher flux across the skin than naproxen, with a maximum enhancement of 3-fold compared to naproxen. Prodrugs 3j-m showed poor aqueous solubility and permeation across the skin.


CONCLUSIONS
Combinations of adequate aqueous solubility and lipophilicity of naproxen aminoacyloxyalkyl prodrugs having fast rates of enzymatic hydrolysis resulted in improved dermal delivery of naproxen.
Rautio
J
J
Department of Pharmaceutical Chemistry, University of Kuopio, Finland. jarkko.rautio@uku.fi
Nevalainen
T
T
Taipale
H
H
Vepsäläinen
J
J
Gynther
J
J
Pedersen
T
T
Järvinen
T
T
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D016503:Drug Delivery Systems; D004355:Drug Stability; D004952:Esters; D005069:Evaluation Studies as Topic; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D009288:Naproxen / Q000008:administration & dosage*; D011355:Prodrugs / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D012869:Skin Absorption; D012995:Solubility; D012996:Solutions
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004952:Esters; D011355:Prodrugs; D012996:Solutions; D009288:Naproxen