Transdermal delivery of zalcitabine: in vitro skin permeation study.
OBJECTIVE
To study the feasibility of transdermal delivery of anti-HIV drugs in order to maintain blood concentration within the therapeutic range for longer duration and to reduce the side-effects associated with high dose administration.


METHODS
The effects of vehicles and enhancers on the skin permeation rate of zalcitabine (ddC) were investigated to determine the maximum permeation rate attainable. In vitro skin permeation of ddC, saturated in various compositions of ethanol/tricaprylin or ethanol/water cosolvent system, with and without enhancer, was studied at 37 degrees C using freshly excised hairless rat skin and human cadaver skin as model skins.


RESULTS
The skin permeation rate of ddC from both ethanol/tricaprylin and ethanol/water cosolvent system increased when increasing the volume fraction of ethanol and reached maximum values at 50-60% (vol/vol) of ethanol. Addition of 1.0% (vol/vol) of permeation enhancer, such as oleic acid or N-methyl-2-pyrrolidone, to the ethanol/tricaprylin (50:50) cosolvent system could not significantly increase the permeation rate of ddC. However, addition of 1.0% (vol/vol) of oleic acid in ethanol/water (60:40) cosolvent system dramatically enhanced the skin permeation rate of ddC with reduced lag time. Permeation rate of ddC increased with increasing oleic acid concentration up to 0.7% (vol/vol) in the ethanol/water (60: 40) cosolvent system, and reached a plateau with further addition of oleic acid. Although permeation rate of ddC across human cadaver skin (0.61 mg/cm2/h) was three times lower than that across hairless rat skin (1.88 mg/cm2/h), the maximum permeation rate of ddC attainable, using ddC saturated solution in ethanol/water (60: 40) cosolvent system containing 1.0% (vol/vol) oleic acid, was 4-5 times higher than the target rate (0.14 mg/cm2/h) to maintain the therapeutic blood level.


CONCLUSIONS
The synergistic enhancement effect of ethanol and oleic acid can make transdermal delivery of ddC feasible.
Kim
D D
DD
Controlled Drug-Delivery Research Center, College of Pharmacy, Rutgers, State University of New Jersey, Piscataway 08854, USA.
Chien
Y W
YW
D000279:Administration, Cutaneous; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D004339:Drug Compounding; D004357:Drug Synergism; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D012869:Skin Absorption / Q000187:drug effects; D016047:Zalcitabine / Q000008:administration & dosage*
D000998:Antiviral Agents; D009829:Oleic Acids; D018894:Reverse Transcriptase Inhibitors; D019301:Oleic Acid; D000431:Ethanol; D016047:Zalcitabine