232 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS ability is confusing and sometimes contradictory because changes in the thermodynamic activity of solute between vehicles were not considered (2,3). In previous studies (4-6), the enhancement in solute flux by aliphatic alcohols through polydimethylsiloxane membranes was investigated. Alcohols were sorbed by the mem- brane, resulting in increases in solute partitioning. Diffusion coefficients were not sig- nificantly changed owing to initially high solute mobility within the "dry" polymer matrix. Saturated solutions maintained constant activity of solute but reduced the ac- tivity of the solvent. Alcohol sorption, and hence membrane interaction, exponentially declined as the alcohol content was reduced. As a result, flux did not increase propor- tionally with solute concentration but instead reached a peak and then declined. Diffu- sion experiments at infinite dilution provided data that generated a "solvent index" allowing solute independent quantitation of permeation enhancement. The delineation of alcohol effects on the synthetic membrane was made possible due to its stability and homogeneity. In this study, similar experiments employing excised fuzzy rat skin have been per- formed. The objectives of this preliminary work include the identification and quanti- tation of interactive solvents, evaluation of concentration effects, and comparison to polydimethylsiloxane interactive systems. Fuzzy rat skin as a model for human skin offers several advantages, including its ready availability, known history, and reduced inter-subject variability. Also, limited studies indicate that the permeability of fuzzy rat skin to n-alkanols is qualitatively similar to that of human skin (7). Heatin Bh ?: ..(. O :.-"e '? 'e i Collection Vials (In Rack) Diffusion Cell Figure 1. Skin permeation apparatus used in this study.
SKIN PENETRATION 233 EXPERIMENTAL MATERIALS The solutes utilized were methylparaben, propylparaben (Fisher Scientific Company, Fairlawn, NJ) and theophylline (Eastman Kodak Company, Rochester, NY). Solute melting points and HPLC chromatograms were used to establish purity. The solvents were distilled water, spectrograde alcohols, propylene glycol, polyethylene glycol 400 (PEG 400), glycerin (Fisher Scientific), and dimethylisosorbide (ICI Americas, Wil- mington, DE). EQUIPMENT A teflon flow-through cell mounted into a temperature controlled aluminum block (Crown Glass, Somerville, NJ) was used in the permeation studies (Figure 1). The body portion of the cell contained the inlet and exit ports and a glass window allowing inspection for air bubbles. Prepared skin was mounted stratum corneum side up in the body of the cell. A cylinder was locked into the cell body (using a threaded ring) and formed the donor compartment. The cylinder was modified by increasing its length in order to reduce skin torque during mounting and to increase donor compartment volume. The area available for diffusion was 0.64 cm 2. Receptor solution was delivered to the cells via a peristaltic pump, and effluent was collected into tared vials. A fraction collector allowed the unattended collection of samples at specified time intervals. METHODOLOGY Male fuzzy rats (Skh:fz Temple University, Philadelphia, PA), 10-weeks-old, weighing 275-300 g, were used in this study. The animals were sacrificed by CO2 asphyxiation. Excised skin samples were stored in a freezer for less than eight weeks. The samples were sufficiently thawed before use, and the dorsal region was removed and dermatomed to a thickness of 320 !xm or 450 !xm (Pagett Dermatome, Kansas City, MO). After gross examination to eliminate damaged skin specimens, the skin was then mounted into the diffusion cell as previously described. The cells were heated to main- tain a 37øC temperature at the dermal side of the skin. The receptor solution was the same throughout the study and consisted of normal saline with 0.25% w/v chlorobu- tanol. The receptor reservoir was maintained at 40øC to reduce formation of air bubbles under the dermal surface. Entrapped air was removed by careful tilting of the cell. Receptor fluid was pumped through the cell at a controlled rate to allow detection of Table I Inter- Versus Intra-Subject Variation in Flux for Aqueous Suspensions of Theophylline (450-•m Skin Thickness) Flux - SD (Ixmol/cm2/h) cv (%) Within an animal (n = 6) Between animals (n = 6) 0.12 -4- 0.02 0.14 + 0.01 12 10
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