A Mechanistic Study of the Effects of the 1 -Alkyl-2-pyrrolidones on Bilayer Permeability of Stratum Corneum Lipid Liposomes: A Comparison with Hairless Mouse Skin Studies zyxwv KUNIO YONETOt5, S. KEVIN LItx, ABDEL-HALIM GHANEM~, DAAN J. A. CROMMELINS, AND WILLIAM I. HIGUCHI~ Received December 19, 1994, from the zyxwvutsrq Qepartment of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84 1 12, #Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands, and §Sekisui Chemical Co., Ltd., Corporate Research Institute, Medical Laboratory, Mishimagun, Osaka, Japan. publication March 28, 1995@. Accepted for Abstract 0 The influence of a series of 1-alkyl-2-pyrrolidones (C*-Cs) on the transport behavior of lipophilic and polarlionic permeants across hairless mouse skin was recently investigated by employing a physical model approach that treats the stratum corneum barrier as a diffusional system of parallel lipoidal and pore pathways. In this previous study, the transport enhancement effects (enhancement factor, EHMS) on the lipoidal pathway of the stratum corneum were found to be essentially the same for all steroidal probe permeants investigated at various concentra- tions of these 1 -alkyl-2-pyrrolidones. In the present research, the relationship between solute transport enhancement in the lipoidal pathway of hairless mouse skin and the transport enhancement in the stratum comeum lipid liposome bilayer was studied by comparing the enhancement factor for the lipoidal pathway in the hairless mouse skin, &MS, with that for the stratum corneum lipid liposome, ESCLL, at equal solution con- centrations of the 1 -alkyl-2-pyrrolidones. The release rates zyxwvutsr of o-mannitol, D-glucose, 3-~methyl-~-glucose, sucrose, and raffinose from stratum corneum lipid liposomes were determined, and the EscLL values for these permeants were compared with the &MS values obtained with hairless mouse skin using the steroidal permeants. An important finding in this study was a semiquantitative correlation between the enhancement effects induced by the l-alkyl-2-pyrrolidones, except l-ethyl-2-pyrrolidone,with the liposome bilayer using sugar molecules as permeants and those found with the lipoidal pathway in hairless mouse skin using steroid molecules as permeants. The enhancement effects on the barrier properties of the liposome bilayer were found to be reversible at the levels of the l-alkyl- 2-pyrrolidones used in the present study. The transport mechanism of the sugar molecules in the liposome bilayer was also investigated, and analyses involving hindered diffusion calculations and a permeability vs partition relationship suggest that partitioning followed by diffusion in the liposome bilayer is the likely major mechanism in the transport of the sugar molecules out of stratum corneum lipid liposomes; this finding is consistent with the semiquantitative correlation found between fHMS and ESCLL. Introduction In recent years, investigations have been aimed a t develop- ing reliable models for mimicking percutaneous absorption across human skin. Artificial membrane systems, such as polymer membranes' and lipid membrane^,^.^ have been studied in attempts to develop model membrane systems which predict and characterize the barrier properties of skin. Other investigator^^,^ have used stratum corneum lipid lipo- somes (SCLL) air-dried on hydrophilic filter disks or sand- wiched between filter supports in attempts to develop relevant models for the epidermal membrane. Recently, Kim et al.'j have used SCLL together with fluorescent probes to study zyxwvu @Abstract published in zyxwvutsrqp Advance ACS Abstracts, May 1, 1995. the effects of n-alkanols on membrane fluidity and found a semiquantitative correlation between fluidity increases in the SCLL membranes and transport enhancement across hairless mouse stratum corneum with the n-alkanols; this correlation suggests that the stratum corneum layer may be investigated a t the molecular level by fluorescence using the SCLL model. Similarly, it suggests that SCLL may be employed as a model for studies of the stratum corneum using other techniques such as IR spectroscopy7 and NMR spectros~opy.~~~ This encouraging finding has led us to further investigation of the possibility of using the SCLL model to better understand the mechanisms of transport enhancement and perhaps, ulti- mately, the general properties of the stratum corneum. The main purpose of this research was to examine the transport behavior of SCLL membranes and answer the following question: is there a correlation between SCLL membrane transport and transport along the lipoidal pathway of hairless mouse skin (HMS)? To this end, we aimed to study the enhancement effects induced by the l-alkyl-2-pyrrolidones z (AP's) on the SCLL membrane permeability and to compare these effects with corresponding data obtained with HMS. Release kinetics of polar nonelectrolytes (molecular weight ranged from 170 to 560) from unilamellar SCLL were to be determined, and the diffision mechanism of these permeants transporting across the liposome bilayer was to be investi- gated. As will be seen, semiquantitative correlations were found between the enhancement effects observed with the SCLL bilayers and those deduced for the lipoidal pathway of HMS. This correlation suggests that SCLL may be considered as a model for the mechanistic studies of the lipoidal pathway in percutaneous absorption. Strategy The transport behavior of SCLL bilayers cannot be com- pared directly with that of HMS due to the different mor- phologies and permeability pathways involved. Recently, a physical model approach for investigating the influences of the short chain n-alkanolslO and of the AP'sll on the transport behavior of lipophilic and polarhonic permeants across HMS was presented. Hydrocortisone, P-estradiol, corticosterone, and tetraethylammonium bromide were the model permeants used in these transport studies. The permeability coefficient of the lipoidal pathway, zyx PL, was calculated from the total permeability coefficient (the permeability coefficient of full thickness skin, PT), the permeability coefficient of the dermis- epidermis combination (the permeability coefficient of stripped skin, PD/E), and the permeability coefficient of the pore pathway (the permeability coefficient of full thickness skin obtained from a tetraethylammonium bromide diffision ex- periment, Pp) using the parallel lipoidal and pore pathway model: 0 1995, American Chemical Sociev and American Pharmaceutical Association 0022-3549/95/3184-0853$09.OO/O Journal of Pharmaceutical Sciences / 853 Vol. zyx 84, No. 7, July 1995