In Vivo Immunomodulatory, Cumulative Skin Irritation, Sensitization and Effect of d-Limonene on Permeation of 6-Mercaptopurine through Transdermal Drug Delivery

Abstract

Using skin as a port for systemic drug administration, transdermal drug delivery has expanded greatly over the last two decades. Our aim was to formulate the single layer drug-in-adhesive transdermal patch for 6-mercaptopurine (6-MP). In vitro permeation study was carried out using modified Franz diffusion cell with and without of different concentration of d-limonene in human cadaver skin. In vivo immunomodulatory was carried out in mice, cumulative skin irritation, sensitization and patch adherence study was done in both mice and human subjects.

Lemon (Citrus limon, Burm.f.) essential oil enhances the trans‐epidermal release of lipid‐ (A, E) and water‐ (B6, C) soluble vitamins from topical emulsions in reconstructed human epidermis

“…However, it is also known that the ratio between ceramides and phospholipids is slightly different between SkinEthic RHE and excised epidermis [43]; therefore, on a quantitative ground, it is difficult to predict which magnitude of vitamins penetration enhancing by lemon oil is to be expected in native epidermis or in vivo. For the sake of comparison, pre‐treatment of human skin from cadaver with d ‐limonene increased its permeability to 5‐fluorouracil by a factor of 3.6 [44], whereas 6% v/w d ‐limonene (equivalent to 10% lemon oil) in the formulation increased the flux of 6‐mercaptopurine by a factor of 5.4 [45], and petitgrain oil ( C. aurantium var. amara), having composition close to that of lemon oil, enhanced the permeability of excised human skin to nitrendipine by a factor of 11 [42] – enhancing effects of the same magnitude as those observed here in RHE, albeit with different molecules.…”

“…Plant essential oils are well‐perceived natural ingredients, and, despite the fact that several terpenoids (including d ‐limonene) are listed among potential allergens, they are generally less toxic or irritant than other skin penetration enhancers (e.g. surfactants) [45, 46]. Therefore, results shown here might be of value in the design of vitamin‐based cosmetic formulations.…”