Transdermal delivery of atenolol: effect of prodrugs and iontophoresis.
Inadequate skin permeability is the main challenge encountered in the transdermal drug delivery and to solve this crisis physical and chemical enhancement techniques are being developed. The aim of the present investigation was to study the combined effect of two such techniques, iontophoresis and esterification, on the transdermal delivery of atenolol. A series of ester prodrugs of atenolol were synthesized, characterized and studied for physicochemical properties and stability. In vitro permeation studies were carried out for atenolol and prodrugs at different donor concentrations (5, 10, and 20 mM) by passive process and iontophoresis (0.5 mA/cm(2)). Evaluation of the physicochemical parameters showed significant increase in lipophilicity and slight reduction in pK value in the ester prodrugs compared to parent drug. Stability studies revealed higher stability at pH 4 than pH 6. Prodrugs significantly enhanced the transdermal flux of atenolol in passive process while in iontophoresis the enhancement ranged from 1.4 to 2.7 fold compared to atenolol. In the prodrug series, permeation rate increased with increase in the length of alkyl side chain up to the addition of 5 carbon units, but thereafter no specific pattern was recorded in both passive and iontophoretic process. The steady state flux was highest in atenolol valerate (1.48 micromol/cm(2) h), which shows the promise of meeting the desired permeation rate (3.0- 31.0 micromol/ h) for maintenance of the therapeutic level in a 70 kg human.
Anroop
B
B
Department of Pharm. Sciences, S.B.S. (PG) Institute of Biomedical Sciences & Research, Dehradun, India. banroop@rediffmail.com
Ghosh
B
B
Parcha
V
V
Khanam
J
J
D000279:Administration, Cutaneous; D000818:Animals; D001262:Atenolol / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000378:metabolism*; D004355:Drug Stability; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D007478:Iontophoresis / Q000379:methods*; D010539:Permeability; D011355:Prodrugs / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000378:metabolism*; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption / Q000502:physiology; D012995:Solubility; D034421:Sus scrofa
D004952:Esters; D011355:Prodrugs; D001262:Atenolol