Enhancement of skin permeation of miconazole by phospholipid and dodecyl 2-(N,N-dimethyl amino)propionate (DDAIP).
Miconazole (MCZ) has very low solubility in both water and oil. Permeation rates through shed snakeskin from an aqueous suspension and a mineral oil suspension were 0.5 microg/cm(2)/h and almost none, respectively. When hydrogenated phosphatidylcholine (HPC) was added to mineral oil and heated to 95 degrees C, the solubility of MCZ increased in proportion to the HPC concentration. DSC measurements also indicated an interaction between them. Thus, a gel formed by hydrogenated phospholipid and mineral oil, as vehicle was prepared. The solubility of MCZ in the gel was around 1% and the permeation rate was 1.3 microg/cm(2)/h, which was about 2.5 times that from an aqueous suspension. As an alternative approach, a skin permeation enhancer, dodecyl 2-(N,N-dimethyl amino)propionate (DDAIP) was applied 2 h before a skin permeation study. The permeation from an aqueous suspension became 11 times that of the suspension without DDAIP pretreatment. The concentration of MCZ in the skin increased 8-fold, indicating that the enhancement effect involved high partition of MCZ into the skin. On the other hand, when a gel formulation was used, pretreatment with DDAIP was not as effective as incorporation of DDAIP in the gel formulation. Following pretreatment, permeation was only two times that of the gel without DDAIP pretreatment, and half that of the water suspension with DDAIP pretreatment. This suggested that release from the gel was the rate-limiting step with the gel formulation. When DDAIP was added to the gel, the permeation rate of MCZ was 3.3 microg/cm(2)/h. It was also a release limited type permeation. The gel with DDAIP is potentially a useful formulation, because of relatively high permeation while possibly avoiding overdosing.
Fujii
M
M
Showa Pharmaceutical University, 3-3165, Machida, Tokyo194-8543, Japan.
Büyüktimkin
S
S
Büyüktimkin
N
N
Rytting
J H
JH
D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D005782:Gels; D066298:In Vitro Techniques; D008825:Miconazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008899:Mineral Oil; D009823:Ointment Bases; D010743:Phospholipids / Q000494:pharmacology*; D012869:Skin Absorption / Q000187:drug effects*; D012911:Snakes; D012995:Solubility; D013268:Stimulation, Chemical; D013535:Suspensions
D000935:Antifungal Agents; D005782:Gels; D009823:Ointment Bases; D010743:Phospholipids; D013535:Suspensions; C085388:dodecyl 2-(N,N-dimethylamino)propionate; D008825:Miconazole; D008899:Mineral Oil; D000409:Alanine