Transdermal delivery of highly lipophilic drugs: In vitro fluxes of antiestrogens, permeation enhancers, and solvents from liquid formulations

• Published in: Pharmaceutical research Vol. 19; no. 5; pp. 661 - 668
• Main Authors: FUNKE, Adrian P, SCHILLER, Roman, MOTZKUS, Hans W, GÜNTHER, Clemens, MÜLLER, Rainer H, LIPP, Ralph
• Format: Journal Article
• Language: English
• Published: New York, NY Springer 01.05.2002; Springer Nature B.V
• Subjects: Adjuvants, Pharmaceutic - pharmacokinetics; Administration, Cutaneous; Animals; Biological and medical sciences; Biological Transport; Calorimetry, Differential Scanning; Chemistry, Pharmaceutical; Diffusion; Dimethyl Sulfoxide - pharmacokinetics; Dose-Response Relationship, Drug; Estradiol - administration & dosage; Estradiol - analogs & derivatives; Estradiol - pharmacokinetics; Estrogen Receptor Modulators - administration & dosage; Estrogen Receptor Modulators - pharmacokinetics; General pharmacology; In Vitro Techniques; Isosorbide - analogs & derivatives; Isosorbide - pharmacokinetics; Lauric Acids - pharmacokinetics; Male; Medical sciences; Mice; Mice, Hairless; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Propylene Glycol - pharmacokinetics; Skin - metabolism; Skin Absorption; Solvents - pharmacokinetics; Sulfur Compounds; Time Factors; Transdermal system; Pharmaceutical technology; Lauric acid; Biological transport; Rodentia; Antiestrogen; Permeation; Partition coefficient; Drug adjuvant; In vitro; Property formulation relationship; Lipophilic compound; Organic solvent; Vertebrata; Mammalia; Mouse; Animal; Dosage form; Fluid form; Skin; Absorption enhancer; Propanediol
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1015314314796

Highly lipophilic basic drugs, the antiestrogens AE 1 (log P = 5.82) and AE 2 (log P = 7.8) shall be delivered transdermally. Transdermal permeation of drugs, enhancers, and solvents from various fluid formulations were characterized by in-vitro permeation studies through excised skin of hairless mice. Furthermore, differential scanning calorimetry (DSC) measurements of skin lipid phase transition temperatures were conducted. Transdermal flux of highly lipophilic drugs was extraordinarily enhanced by the unique permeation enhancer combination propylene glycol-lauric acid (9 + 1): steady-state fluxes of AE 1 and AE 2 were as high as 5.8 microg x cm(-2) x h(-1) and 3.2 microg x cm(-2) x h(-1), respectively. This dual enhancer formulation also resulted in a marked increase in the transdermal fluxes of the enhancers. Furthermore, skin lipid phase transition temperatures were significantly reduced by treatment with this formulation. Transdermal delivery of highly lipophilic drugs can be realized by using the permeation enhancer combination propylene glycol-lauric acid. The extraordinary permeation enhancement for highly lipophilic drugs by this formulation is due to mutual permeation enhancement of these two enhancers and their synergistic lipid-fluidising activity in the stratum corneum.