Ceramide, which consists of long-chain amino alcohol and long-chain fatty acids, forms the backbone of sphingolipids; i.e., phosphosphingolipid and glycosphingolipid. While ceramide is a minor constituent in the cellular membrane, heterogeneous molecular species of ceramide, which are due to variations in amide-linked fatty acids (carbon chain length and hydroxylation) and sphingoid bases, contribute to epidermal permeability in the extracellular domain of the outmost layer of skin, the stratum corneum. In addition to their structural roles, ceramide and its metabolites, such as sphigosine-1-phosphate and ceramide-1-phosphate, serve as modulator lipids to maintain normal cellular functions.

The skin consists of at least three compartments, epidermis, dermis, and hypodermis. Stratum corneum outside of epidermis generally acts as a physical barrier for transdermal absorption of most of therapeutic agents after topical application, whereas biological barrier may also exist at epidermis and dermis. Recent studies have clarified functional expression of a variety of transporters in the latter barrier. Transporters involved in dermal homeostasis could be a target of novel therapeutic agents. On the other hand, a certain type of anticancer agents exhibit severe dermal toxicity after systemic administration, and transporters may play fundamental role in their dermal distribution and toxicity. In this chapter, we summarized the latest information on which transporters are expressed in the skin. Their possible involvement in dermal homeostasis, transdermal absorption after topical application, and dermal distribution after systemic administration of therapeutic agents will also be discussed.

Organisms developed epithelium separating intra and outer body in the evolution from unicellular to multicellular organisms. Intercellular spaces are sealed by tight junctions (TJs) between the adjacent cells. TJs exhibit barrier-function to prevent leakage of solutes in the intercellular spaces and fence-function to maintain apical and basolateral localization of lipids and membrane proteins in the epithelium. Occludin, claudin family members, and tricellulin, which were identified by Dr. Tsukita's group, are key components for the TJ-functions. Disruption of the TJ-functions is frequently observed in pathological conditions, such as carcinogenesis, inflammation, and infections. In this review on the skin, we introduce the molecular structure of TJ-seals in the skin, and we also overview recent findings on the involvement of TJs in some skin diseases.

Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disorder characterized by systemic hamartomas with neuropsychiatric symptoms called TAND (TSC-associated neuropsychiatric disorders), and hypomelanotic macules. TSC is caused by genetic mutations in either TSC1 or TSC2 gene which encodes hamartin and tuberin, respectively. As the hamartin-tuberin-complex down-regulates mechanistic/mammalian target of rapamycin complex1 (mTORC1), dysfunction of hamartin or tuberin induces the constitutive activation of mTORC1. Almost all the symptoms in TSC are derived from the activation of mTORC1. mTORC1 inhibitor, rapamycin/sirolimus, improves all the symptoms including facial angiofibroma. Investigation of pathogenesis of the disease and progress of diagnostic technology have contributed to discover TSC patients showing slight symptoms without neural disorders. Skin lesions frequently affect the patients and impair QOL of patients. Among the skin lesions, facial angiofibromas should be indispensably treated because they may become large and disfiguring and often damage the QOL of patients.Surgical therapies have been the only established treatment for TSC skin legions, which are difficult to perform on small children and patients with intellectual disabilities. To solve the problem, inhibitors of mTORC1 have recently emerged as a remedy for TSC. Although systemic administration of mTORC1 inhibitors are effective for all symptoms with TSC, adverse effects also extend to the whole body. Then, to reduce the adverse effects caused by the systemic administration of mTORC1 inhibitors, sirlimus, we developed topical sirolimus formulation against the skin lesion of TSC. We conducted phase 2 and 3 randomized clinical trials by the topical sirolimus treatment with the sirolimus gel formulations in TSC patients and showed significant reductions in the size and color of the angiofibromas. In addition to the current state of TSC, the efficacy, safety and future problems of topical sirolimus formulation as a remedy for TSC skin lesions and its future problems are discussed.

In recent years, there is a growing need for nucleic acid medicines targeting intractable skin diseases such as atopic dermatitis. Human skin is an available organ with the largest surface area for noninvasive drug administration. However, the intradermal permeability of hydrophilic and high molecular weight substances such as siRNA is strongly limited by the barrier function of the skin. Here, we introduce the siRNA delivery researches for skin disease treatment.

Seborrheic keratosis is characterized as sharply demarcated brownish plaques with verrucous surfaces. This lesion is considered unattractive and disfiguring and may have negative psychological impacts. Thus, they are often removed for cosmetic reasons by surgical treatments, such as cryotherapy and laser surgery. However, these treatments require regular outpatient treatments for complete removal of the lesions, incurring high costs. Drug therapy for seborrheic keratosis is an attractive treatment option for self-treatment at home but is not well established, because skin permeability of candidate ingredients for seborrheic keratosis is relatively low by keratinaization of stratum corneum. In this review, we introduce the development of a novel drug therapy using a self-dissolving microneedle patch which can directly deliver candidate ingredients to the epidermis by puncturing the stratum corneum.

Pharmaceutical application of ionic liquids (ILs), which are commonly defined as salt compounds composed of ionic species and melt below 100℃, is an attractive research field in a drug delivery system (DDS). The solubilization ability for insoluble drug molecules is a promising property of ILs. In 2010, it was reported that acyclovir, a sparingly soluble drug, was dissolved in imidazolium-based ILs, and the IL-in-oil microemulsions enhanced the transdermal delivery of acyclovir. The transdermal delivery is the most studied DDS field using ILs and some hydrophobic ILs were confirmed as skin penetration enhancers due to its higher interaction with the hydrophobic skin surface barrier. Utilization of active pharmaceutical ingredients (API) as the ions of ILs is known as an alternative strategy of IL-based DDSs because the API-IL enables to tune their physical or chemical properties of ILs. To improve the transdermal delivery, drugs were robed with hydrophobic counter ions. Recently, biocompatibility has been regarded as one of the most important properties of ILs for the DDS application. Several biomolecule-derived ions such as choline and amino acids were reported to form ILs and the biocompatible ILs were used as a solvent for solubilizing poorly soluble drugs and skin penetration enhancers. These researches suggest that ILs would be a promising solvent for developing a novel DDS.