Stratum corneum permeability studies

Confining their study to monofunctional molecules, Roberts et al. [38] compared seven different models for predicting human stratum corneum permeability coefficients. The performance of the models was assessed by the adjusted coefficient of determination r2dj and the Akaike Information Criterion (AIC) [39], Both r2dj and AIC allow for comparing models with different numbers of variables (degrees of freedom). Exclusion of polyfunctional molecules led to a comparatively small set of only 24 molecules. The previously reported... 

Additional instrumental techniques are now being used in conjunction with the traditional permeability experiments to probe the physical structures of the stratum corneum. These studies are contributing to the understanding of the molecular structure, conformation and order of the stratum corneum and its components. 

An additional variable that must be accounted for in derma absorption studies that may overshadow the difference between chemicals Is body site differences in absorption within a species. Regional variation in skin permeability at different body. sites may be related to skin thickne.ss, number of cell layers, cell size of the epidermis and stratum comeum, and di.stribution of hair follicles and sweat pores. Because of thick layers of stratum corneum, permeability in palmar and plantar skin is expected to be less than that in the scalp or forearm (Feldmann and Maibach, 1974). Data from several studies suggc.st that regional variation in vascular anatomy and blood flow should also be considered (Montciro-Rivicrc o/.. 1990 Qiao cf a/.. 1993). 

Because of the possible effects of active and carrier-mediated processes and metabolic biotransformation, the issue of tissue viability is important for in vitro buccal mucosal experiments. The barrier nature of the buccal mucosa resides in the upper layers of the epithelium, where unlike in the stratum corneum, the cells contain a variety of functional organelles [119, 122, 125, 150], and so tissue viability may be an important component of the barrier function of the tissue. Various methods have been employed to assess the viability of excised buccal mucosa, including measurement of biochemical markers, microscopic methods, and linearity of transport data [42], While biochemical methods, including measurement of adenosine 5 -triphosphate (ATP) levels and utilization of glucose, provide information on the metabolic activity of the tissue, this does not necessarily relate to the barrier function of the tissue. In excised rabbit buccal mucosa, levels of ATP were measured and found to decline by 40% in 6 h, and this correlated well with transmission electron microscopic evaluation of the tissue (intact superficial cells) [32], In addition, the permeability of a model peptide was unaltered up to 6 h postmortem, but at 8 h, a significant change in permeability was observed [32], These investigators therefore claimed that excised rabbit buccal mucosa could be used for diffusion studies for 6 h. 

A. Schatzlein and G. Cevc. Non-uniform cellular packing of the stratum corneum and permeability barrier function of intact skin a high-resolution confocal laser scanning microscopy study using highly deformable vesicles (Transfersomes). Br. J. Dermatol. 138 583-592 (1998). 

Relatively little is known about the structure of stratum corneum, even though it is considered the primary barrier in transdermal permeation of most permeants. Traditional permeability studies of full-thickness skin (1-12) have implied molecules permeated through the skin by various polar or nonpolar pathways depending on the hydrophilicity or lipophilicity of the permeant. Coupling of macroscopic and molecular-level investigations of thermally induced alterations of the stratum corneum are beginning to provide insight into the molecular structure and barrier function of the stratum corneum. 

Michaels et al (5) further studied the barrier effects of the skin in terms of the composition of the pathways, as well as the microstructure, permeability and permselectivity of the particular pathways. In particular, the barrier to permeation in the stratum corneum was attributed not only to the interstitial lipids, but also to their structure as ordered multilayers for nonpolar alkanols. 

Permeability changes in full-thickness skin have been associated with temperature or solvent pretreatment. The molecular basis of these permeability changes has been attributed to lipid melting or protein conformational changes. The current studies have probed the role of lipid fluidity in the permeability of lipophilic solutes, and examined the effects of temperature on the physical nature of the stratum corneum by differential scanning calorimetry and thermal perturbation infrared spectroscopy. Combining molecular level studies that probe the physical nature of the stratum corneum with permeability results, a correlation between flux of lipophilic solutes and nature of the stratum corneum barrier emerges. 

Permeability studies coupled with differential scanning calorimetry and thermal perturbation infrared spectroscopy investigations of the stratum corneum and its lipid and protein components have enabled the physical structure of the stratum corneum to be probed on a molecular level. 

Thermally induced permeability enhancement of the more lipophilic solutes (butanol, octanol and hydrocortisone) through hairless mouse stratum corneum occurred in the temperature range also associated with lipid transitions in the calorimetry studies. Therefore, it seems likely enhanced permeabilities and lipid mobility within the stratum corneum are correlated. However, these macroscopic studies are unable to provide more specific information concerning the molecular origins of the thermal transitions. The studies provide even less information concerning possible irreversible alterations of the keratinized protein components of the stratum corneum. 

The stratum corneum basically contains a mixture of cholesterol, free fatty acids, and ceramides, placed in multilayers. They mediate both the epidermal permeability barrier and the transdermal delivery of both lipophilic and hydrophilic molecules. Studies have shown that each of the three key lipid classes is required for normal barrier function (32). These reports also show the potential of certain inhibitors of lipid synthesis to enhance the trans-dermal delivery of drugs like lido-caine or caffeine. Thus, the modulation of stratum corneum lipids is an important determinant of the barrier permeability to both hydrophobic and hydrophilic compounds transport and drug penetration. It has been reported that an inverse correlation exists between solute penetration and stratum corneum lipid content (33). 

Skin is naturally covered with protective lipophilic oils, and the outer layer of the skin, the stratum corneum, is also lipophilic. I4 5 As a result, lipophilic chemicals are absorbed through skin at higher rates than hydrophilic species and permeability is directly related to A w, as demonstrated by the following two studies. In the first, the permeabilities of a homologous series of parabens across excised guinea pig dorsal skin increased with increasing Kqw values as follows ... 

It has been known for some time that the intercellular lipids of the stratum corneum play a very important role in the skin barrier function. This knowledge has been accumulated from systematic studies on skin permeability of compounds of varying lipophilicity (Scheuplein 1965 Roberts et al. 1977 Durrheim et al. 1980 Surber et al. 1993) and investigations of alterations in transepidermal water loss (Elias and Feingold 1992 Aszterbaum et al. 1992). Because the major route of permeation across the stratum corneum is via the intercellular lipid, the rate at which permeation occurs is largely dependent on the physicochemical characteristics of the penetrant, the most important of which is the relative ability to partition into the intercellular lamellae. 

Since percutaneous permeation studies are frequently conducted using laboratory animal models such as rats, mice, and guinea pigs, it should be understood that wide dilferences exist between these models, including the thickness of the stratum corneum, the number of sweat glands and hair follicles, and the distribution of the papillary blood supply. These factors affect both the routes of transport and the resistance to penetration. In addition, the human skin differs from different animal species in biochemical composition and permeability. The subtle biochemical differences between human and animal skin may alter the reaction between permeant molecules and the skin [37]. 

The cubic and hexagonal phases based on GMO/water and GMO/oleic acid/ water, respectively, are well studied and were shown to have the ability to sustain the release of incorporated compounds [59, 67, 68]. Moreover, each component constructing either the cubic or the hexagonal phase is a penetration enhancer by itself. GMO is known to promote ceramide extraction and enhancement of lipid fluidity in the stratum corneum, and oleic acid is considered to increase epidermal permeability via a mechanism involving perturbation of the stratum corneum lipid bilayers and lacunae formation [69]. 

Regional differences in permeability of skin largely depend on the thickness of the intact stratum corneum (Wester and Maibach 1989). According to the findings of a study by Feldmann and Maibach (1967), the highest total absorption of hydrocortisone is that from the scrotum, followed (in decreasing order) by absorption from the forehead, scalp, back, forearms, palms and plantar surfaces. 

Numerous studies have attempted to elucidate the effect of skin penetrants by thermal analysis. Kaplun-Frischoff and Touitou [182] showed that methanol decreased the melting peaks of cholesteryl oleate and ceramides and modified the DSC of isolated stratum comeum this alters its barrier properties. Similarly a soybean-lecithin micro-emulsion gel was shown to affect the stratum comeum lipid organisation by FTIR and DSC [186] and hydroxypropyl-P-cyclodextrin can increase the permeability of the stratum corneum, possibly as a result of lipid extraction that induced modest changes in the stratum comeum lipid transition temperature [179]. 

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