title: Elasticity of vesicles affects hairless mouse skin structure and permeability.
abstract: One of the possibilities for increasing the penetration rate of drugs through the skin is the use of vesicular systems. Currently, special attention is paid to the elastic properties of liquid-state vesicles, which are supposed to have superior properties compared to gel-state vesicles with respect to skin interactions. In this study, the effects of vesicles on hairless mouse skin, both in vivo and in vitro, were studied in relation to the composition of vesicles. The interactions of elastic vesicles containing the single chain surfactant octaoxyethylene laurate-ester (PEG-8-L) and sucrose laurate-ester (L-595) with hairless mouse skin were studied, in vivo, after non-occlusive application for 1, 3 and 6 h. The skin ultrastructure was examined by ruthenium tetroxide electron microscopy (TEM) and histology. The extent, to which vesicle constituents penetrated into the stratum corneum, was quantified by thin layer chromatography (TLC). The interactions of the elastic vesicles containing PEG-8-L and L-595 surfactants were compared with those observed after treatment with rigid vesicles containing the surfactant sucrose stearate-ester (Wasag-7). Furthermore, skin permeability experiments were carried out to investigate the effect of treatment with PEG-8-L micelles, elastic vesicles (containing PEG-8-L and L-595 surfactants) or rigid Wasag-7 vesicles on the 3H(2)O transport through hairless mouse skin, in vitro, after non-occlusive application. Treatment of hairless mouse skin with the elastic vesicles affected the ultrastructure of the stratum corneum: distinct regions with lamellar stacks derived from the vesicles were observed in intercellular spaces of the stratum corneum. These stacks disrupted the organization of skin bilayers leading to an increased skin permeability, whereas no changes in the ultrastructure of the underlying viable epidermis were observed. Treatment with rigid Wasag-7 vesicles did not affect the skin ultrastructure or skin permeability. TLC measurements showed that after 1 h of non-occlusive application of elastic or rigid vesicles, a six-fold increased amount of elastic vesicle material was present within the stratum corneum compared to rigid vesicle material. After 3 and 6 h of application the amount of PEG-8-L vesicle material in SC decreased to approximately three- and two-fold, respectively, compared to Wasag-7 vesicle material. Pretreatment of the hairless mouse skin with the elastic vesicles containing 70 mol% PEG-8-L increased the diffusion of 3H(2)O with an optimum application dose of 2.5 mg lipids/cm(2) compared to PBS pretreatment. No significant difference in the enhancement of the 3H(2)O-diffusion was observed between PEG-8-L micelles or elastic vesicles containing 30 or 70 mol% PEG-8-L. Pretreatment with the rigid Wasag-7 vesicles decreased the diffusion rate of 3H(2)O, most probably by the formation of a lipid layer on the skin surface. The effect of the elastic vesicles on the skin permeability is supported by the ultrastructural changes observed by TEM in the intercellular lipid domains. The elastic vesicles containing 70 mol% PEG-8-L disorganize the lipid bilayers thereby creating or modifying pathways for possible drug penetration.
authors.affiliation: Department of Pharmaceutical Technology, Leiden Amsterdam Center for Drug Research, University of Leiden, P.O. Box 9502, 2300 RA, Leiden, Netherlands.
authors.forename: B A
authors.initials: BA
authors.lastname: van den Bergh
authors.forename: J A
authors.initials: JA
authors.lastname: Bouwstra
authors.forename: H E
authors.initials: HE
authors.lastname: Junginger
authors.forename: P W
authors.initials: PW
authors.lastname: Wertz
mesh_terms: D000818:Animals; D002855:Chromatography, Thin Layer; D018699:Coated Vesicles / Q000737:chemistry*; D004548:Elasticity; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008854:Microscopy, Electron; D010539:Permeability / Q000187:drug effects*; D012867:Skin / Q000378:metabolism* / Q000648:ultrastructure*; D012879:Skin Physiological Phenomena / Q000187:drug effects*; D013501:Surface-Active Agents / Q000494:pharmacology; D013997:Time Factors; D014867:Water / Q000378:metabolism
chemical_list: D013501:Surface-Active Agents; D014867:Water