Controlled transdermal delivery of fentanyl: characterizations of pressure-sensitive adhesives for matrix patch design.

Transdermal delivery of fentanyl from various adhesive matrix formulations to achieve a steady-state skin flux was investigated. For this purpose, various pressure-sensitive adhesives selected from the three chemical classes of polymers (polyisobutylene (PIB), acrylate, and silicone adhesives) were characterized with respect to fentanyl's solubility, diffusion coefficient, and permeability coefficient. The solubility of fentanyl in various pressure-sensitive adhesives at 32 degrees C was determined by the drug absorption-desorption method. The solubilities of fentanyl in these adhesives were in the following order: acrylate > silicones > PIB. The permeability coefficient and diffusion coefficient of fentanyl in these adhesives were determined by the membrane diffusion method. The diffusion coefficient rank order was silicone-2920 > silicone-2675 > or = acrylate > PIB. The release profiles of fentanyl in the aqueous buffer from these adhesives with 2-4% drug loading was evaluated. The release rate of fentanyl from the acrylate polymer was significantly higher than those of silicone and PIB adhesives. The in vitro flux of fentanyl through cadaver skin from various adhesives with 2% drug loading was determined at 32 degrees C using modified Franz diffusion cells. The skin fluxes of fentanyl from silicone-2920 and PIB adhesives were 6.3 +/- 0.7 and 3.1 +/- 0.3 micrograms/cm2/h, respectively. On the other hand, the skin fluxes of fentanyl from acrylate and silicone-2675 adhesive matrices were about 1 microgram/cm2/h. The effect of drug loading on skin flux was investigated using PIB as a model adhesive. The drug released in the phosphate buffer (pH = 6.0) increased linearly as the drug loading in the PIB was increased from 1% to 4%; and as the drug loading exceeded 4%, an initial burst effect followed by a zero-order release was observed. The skin flux of fentanyl increased proportionally as the drug loading in the PIB adhesive was increased from 1 to 4%, and a plateau was reached beyond 4% drug loading. These results suggest that fentanyl concentration in the PIB adhesive might have reached saturation above 4% drug loading and that the optimum skin flux was accomplished from such a system because of attainment of maximum thermodynamic activity.

Transdermal drug delivery: useful paradigms.

The successful development of transdermal delivery systems requires a systematic evaluation and understanding of a number of complex phenomena. For example, the study of drug transport through skin (and other biomembranes) has lead to a significant advance in our ability to select drugs which are appropriate for transdermal delivery. Drug release from the transdermal system is also crucial to effective drug delivery and provides a clear opportunity for research in adhesion, polymer physical chemistry, mass transport, and film coating, to name a few. The incorporation of several disciplines into transdermal science holds the exciting promise to provide rapid advances in this technology.

Interaction of hydrocortisone with model membranes containing phospholipid and cholesterol.

Pure and mixed monolayers of lecithin and cholesterol were spread on substrates of dissolved hydrocortisone at 25 and 37 degrees. The presence of hydrocortisone increased the surface pressure of dipalmitoyl and egg lecithin films that were in head contact. The increase in surface pressure was dependent on steroid concentration. There were no significant interactions with coherent cholesterol monolayers. Penetration of hydrocortisone was decreased by the addition of cholesterol to the monolayer system. These model membrane systems indicate that hydrocortisone interacts with the hydrated polar head group of the phospholipid and not with films whose molecules are in hydrocarbon tail contact.

Molecular arrangement in monolayers containing cholesterol and dipalmitoyl lecithin.

The molecular arrangement of dipalmitoyl lecithin and cholesterol in mixed monolayers was investigated with the aid of a physical model. The two lipids are miscible at the surface, but there is no indication of a specific interaction. In equimolar mixed monolayers at 25 and 37 degrees, the lipids are in tail contact. Lecithin molecules are able to remain hydrated in the mixed monolayers at high values of surface pressure.