In vivo deposition of polar molecules from various topical formulations into hairless and hairy rat skin.

Abstract

The major objective of these studies was to examine the in vivo permeation of polar molecules through hairless and hairy rat skin upon topical application of various formulations. The deposition of progesterone, a small lipophilic molecule, was also investigated in order to contrast the results with those of polar penetrants. Finally, formulation factors influencing deposition of a topically applied polar macromolecule, a monoclonal antibody to doxorubicin (MAD11), were assessed. Our major conclusions were: (1) Hairless rodent skin acted as a leaky barrier to mannitol, a prototypical polar permeant, after either in vitro or in vivo topical application of simple aqueous solutions or liposomal dispersions. In vitro conditions exaggerated the transport, which may have been a result of excessive hydration. (2) Differences in permeation of hairless and hairy rat skin may be partly explained by gross histological differences between the species. Hairless rat skin seemed to have been leaky due to cysts, numerous, enlarged sebaceous glands and underdeveloped hair follicles. Fully developed hair follicles in hairy rat skin seemed to act as drug depots for liposome-associated molecules, whereas systemic transport may have been restricted by the deep location of small follicle-associated sebaceous glands. Deposition of liposomal carboxyfluorescein was visualized in the stratum corneum and upper portion of hair follicles by confocal microscopy. Regardless of formulation, only transient fluorescence was visualized throughout hairless rat hair follicles. (3) Localized and systemic deposition of progesterone was greater in hairless rat skin than in hairy rat skin, which again may reflect the presence of enlarged sebaceous glands and cysts in hairless rat skin. (4) Acetone-induced delipidization of the stratum corneum dramatically increased mannitol transport through hairy rat skin, but not hairless rat skin. The results suggest that the treatment failed to completely remove sebaceous lipids from hairless rat skin, which may have a greater overall lipoidal character. (5) The primary factor influencing liposomal deposition of MAD11 into hairless and hairy rat skin was liposome surface charge. Enhanced deposition was observed to a lesser degree by phospholipid liposome particle size reduction and by lipid concentration optimization for nonionic lipid-based liposomes.